Modulation of PTPN13 expression

ABSTRACT

Compounds, compositions and methods are provided for modulating the expression of PTPN13. The compositions comprise oligonucleotides, targeted to nucleic acid encoding PTPN13. Methods of using these compounds for modulation of PTPN13 expression and for diagnosis and treatment of disease associated with expression of PTPN13 are provided.

FIELD OF THE INVENTION

[0001] The present invention provides compositions and methods for modulating the expression of PTPN13. In particular, this invention relates to compounds, particularly oligonucleotide compounds, which, in preferred embodiments, hybridize with nucleic acid molecules encoding PTPN13. Such compounds are shown herein to modulate the expression of PTPN13.

BACKGROUND OF THE INVENTION

[0002] The process of phosphorylation, defined as the attachment of a phosphate moiety to a biological molecule through the action of enzymes called kinases, represents one course by which intracellular signals are propagated resulting finally in a cellular response. Within the cell, proteins can be phosphorylated on serine, threonine or tyrosine residues and the extent of phosphorylation is regulated by the opposing action of phosphatases, which remove the phosphate moieties. While the majority of protein phosphorylation within the cell is on serine and threonine residues, tyrosine phosphorylation is modulated to the greatest extent during oncogenic transformation and growth factor stimulation (Zhang, Critical Review in Biochemistry and Molecular Biology, 1998, 33, 1-52).

[0003] Because phosphorylation is such a ubiquitous process within cells and because cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that a number of disease states and/or disorders are a result of either aberrant activation of, or functional mutations in, kinases and phosphatases. Consequently, considerable attention has been devoted recently to the characterization of tyrosine kinases and tyrosine phosphatases.

[0004] PTPN13 (also known as protein tyrosine phosphatase, non-receptor type 13, Fas associated phosphatase 1; FAP-1, PTP-BAS, protein tyrosine phosphatase 1E; PTP1E, PTPL1) has been cloned from human basophils (Maekawa et al., FEBS Lett., 1994, 337, 200-206), a human glioma cell line (Saras et al., J. Biol. Chem., 1994, 269, 24082-24089) and a human breast carcinoma cell line (Banville et al., J. Biol. Chem., 1994, 269, 22320-22327), and has been mapped to chromosome 4q21 (Inazawa et al., Genomics, 1996, 31, 240-242; van den Maagdenberg et al., Cytogenet. Cell Genet., 1996, 74, 153-155).

[0005] Maekawa et al. have presented evidence for alternative splicing producing at least 3 different isoforms of PTPN13 as a result of in-frame deletions of nucleotides 3229-3285 (PTPN13 type 2) and 2713-3285 (PTPN13 type 3) (Maekawa et al., FEBS Lett., 1994, 337, 200-206). Banville et al. have found five different PTPN13 mRNAs, denoted types 1-5, in human breast carcinoma cells and HeLa cells (Banville et al., J. Biol. Chem., 1994, 269, 22320-22327).

[0006] Disclosed and claimed in U.S. Pat. No. 5,821,075 and corresponding PCT publication WO 95/06735, are isolated nucleic acid sequences encoding PTPN13 and a nucleic acid molecule complementary to said nucleic acid sequences (Gonez et al., 1995; Gonez et al., 1998).

[0007] Disclosed and claimed in U.S. Pat. No. 5,747,245 and corresponding PCT publication WO 95/34661 are nucleic acid sequences encoding human PTPN13 type 4 and type 5 as well as mouse PTPN13 type 5a. Additionally claimed in the same patent and PCT publication are vectors comprising said sequences and isolated nucleotide sequences, comprising at least ten nucleotides that hybridize under relatively stringent conditions to said nucleic acid molecules wherein said relatively stringent conditions allow hybridization to a nucleic acid molecule encoding a PTPN13 type 4 or a PTPN13 type 5, but not to another nucleic acid molecule (Reed, 1995; Reed and Sato, 1998).

[0008] Expression of human PTPN13 is high in kidney, placenta, ovaries and testes and moderate in lung, pancreas, prostate and brain (Saras et al., J. Biol. Chem., 1994, 269, 24082-24089).

[0009] The unique features of the PTPN13 gene product are a leucine zipper motif, a region homologous to the band 4.1 protein, a series of five GLGF (glycine, leucine, glycine, phenylalanine) repeats, and a carboxy-terminal protein tyrosine phosphatase (PTP) domain. Since the function of the proteins of the band 4.1 family is to provide anchors for cytoskeletal proteins at the inner surface of the plasma membrane, PTPN13 has been suggested to form dimers and localize to the submembraneous cytoskeleton (Saras et al., J. Biol. Chem., 1994, 269, 24082-24089).

[0010] PTPN13 interacts with a negative regulatory domain in Fas which inhibits Fas-induced apoptosis (Sato et al., Science, 1995, 268, 411-415). Several investigations have identified PTPN13 as a candidate gene for induction of Fas-mediated apoptosis resistance in various cancers including ovarian cancer (Meinhold-Heerlein et al., Am. J. Pathol., 2001, 158, 1335-1344), pancreatic cancer (Elnemr et al., Int. J. Oncol., 2001, 18, 311-316; Ungefroren et al., Ann. N.Y. Acad. Sci., 1999, 880, 243-251; Ungefroren et al., Cancer Res., 1998, 58, 1741-1749), oral carcinoma (Itakura et al., Int. J. Oncol., 2000, 16, 591-597), hepatocellular carcinoma (Lee et al., Hum. Pathol., 2001, 32, 250-256) and breast cancer (Freiss et al., Molecular Endocrinology, 1998, 12, 568-579). In addition, the Fas-mediated apoptosis resistance role of PTPN13 has been associated with human T cell leukemia virus type 1 (HTLV-I)-associated myelopathy/tropical spastic paraparesis (Arai et al., AIDS Res. Hum. Retroviruses, 1998, 14, 261-267).

[0011] The involvement of PTPN13 in cell signaling events and particularly its role in resistance to Fas-mediated apoptosis make it a potentially useful therapeutic target for intervention in hyperproliferative disorders, disorders arising from aberrant apoptosis, and autoimmune disorders.

[0012] An antisense PTPN13 RNA vector has been used to decrease the levels of PTPN13 in studies of the role of PTPN13 as a trigger of negative proliferation signals in breast cancer cells (Freiss et al., Molecular Endocrinology, 1998, 12, 568-579).

[0013] A synthetic acetylated tripeptide known as Ac-SLV was employed to modulate the function of PTPN13 by competing with Fas for interaction with PTPN13 in investigations of the regulatory role of PTPN13 in Fas-induced apoptosis in thyrocytes (Myc et al., Endocrinology, 1999, 140, 5431-5434).

[0014] Currently, there are no known therapeutic agents which effectively inhibit the synthesis of PTPN13.

[0015] To date, investigative strategies aimed at modulating PTPN13 function have involved the use of antisense vectors, and the synthetic peptide Ac-SLV. However, they have yet to be tested as therapeutic protocols.

[0016] Consequently, there remains a long felt need for agents capable of effectively inhibiting PTPN13 function.

[0017] Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of PTPN13 expression.

[0018] The present invention provides compositions and methods for modulating PTPN13 expression, including modulation of splice variants of PTPN13, including PTPN13 type 1, type 2, type 3, type 4 and type 5.

SUMMARY OF THE INVENTION

[0019] The present invention is directed to compounds, especially nucleic acid and nucleic acid-like oligomers, which are targeted to a nucleic acid encoding PTPN13, and which modulate the expression of PTPN13. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of screening for modulators of PTPN13 and methods of modulating the expression of PTPN13 in cells, tissues or animals comprising contacting said cells, tissues or animals with one or more of the compounds or compositions of the invention. Methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of PTPN13 are also set forth herein. Such methods comprise administering a therapeutically or prophylactically effective amount of one or more of the compounds or compositions of the invention to the person in need of treatment.

DETAILED DESCRIPTION OF THE INVENTION

[0020] A. Overview of the Invention

[0021] The present invention employs compounds, preferably oligonucleotides and similar species for use in modulating the function or effect of nucleic acid molecules encoding PTPN13. This is accomplished by providing oligonucleotides which specifically hybridize with one or more nucleic acid molecules encoding PTPN13. As used herein, the terms “target nucleic acid” and “nucleic acid molecule encoding PTPN13” have been used for convenience to encompass DNA encoding PTPN13, RNA (including pre-mRNA and mRNA or portions thereof) transcribed from such DNA, and also cDNA derived from such RNA. The hybridization of a compound of this invention with its target nucleic acid is generally referred to as “antisense”. Consequently, the preferred mechanism believed to be included in the practice of some preferred embodiments of the invention is referred to herein as “antisense inhibition.” Such antisense inhibition is typically based upon hydrogen bonding-based hybridization of oligonucleotide strands or segments such that at least one strand or segment His cleaved, degraded, or otherwise rendered inoperable. In this regard, it is presently preferred to target specific nucleic acid molecules and their functions for such antisense inhibition.

[0022] The functions of DNA to be interfered with can include replication and transcription. Replication and transcription, for example, can be from an endogenous cellular template, a vector, a plasmid construct or otherwise. The functions of RNA to be interfered with can include functions such as translocation of the RNA to a site of protein translation, translocation of the RNA to sites within the cell which are distant from the site of RNA synthesis, translation of protein from the RNA, splicing of the RNA to yield one or more RNA species, and catalytic activity or complex formation involving the RNA which may be engaged in or facilitated by the RNA. One preferred result of such interference with target nucleic acid function is modulation of the expression of PTPN13. In the context of the present invention, “modulation” and “modulation of expression” mean either an increase (stimulation) or a decrease (inhibition) in the amount or levels of a nucleic acid molecule encoding the gene, e.g., DNA or RNA. Inhibition is often the preferred form of modulation of expression and mRNA is often a preferred target nucleic acid.

[0023] In the context of this invention, “hybridization” means the pairing of complementary strands of oligomeric compounds. In the present invention, the preferred mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases (nucleobases) of the strands of oligomeric compounds. For example, adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bonds. Hybridization can occur under varying circumstances.

[0024] An antisense compound is specifically hybridizable when, binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid to cause a loss of activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target nucleic acid sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, and under conditions in which assays are performed in the case of in vitro assays.

[0025] In the present invention the phrase “stringent hybridization conditions” or “stringent conditions” refers to conditions under which a compound of the invention will hybridize to its target sequence, but to a minimal number of other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances and in the context of this invention, “stringent conditions” under which oligomeric compounds hybridize to a target sequence are determined by the nature and composition of the oligomeric compounds and the assays in which they are being investigated.

[0026] “Complementary,” as used herein, refers to the capacity for precise pairing between two nucleobases of an oligomeric compound. For example, if a nucleobase at a certain position of an oligonucleotide (an oligomeric compound), is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, said target nucleic acid being a DNA, RNA, or oligonucleotide molecule, then the position of hydrogen bonding between the oligonucleotide and the target nucleic acid is considered to be a complementary position. The oligonucleotide and the further DNA, RNA, or oligonucleotide molecule are complementary to each other when a sufficient number of complementary positions in each molecule are occupied by nucleobases which can hydrogen bond with each other. Thus, “specifically hybridizable” and “complementary” are terms which are used to indicate a sufficient degree of precise pairing or complementarity over a sufficient number of nucleobases such that stable and specific binding occurs between the oligonucleotide and a target nucleic acid.

[0027] It is understood in the art that the sequence of an antisense compound need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable. Moreover, an oligonucleotide may hybridize over one or more segments such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure or hairpin structure). It is preferred that the antisense compounds of the present invention comprise at least 70% sequence complementarity to a target region within the target nucleic acid, more preferably that they comprise 90% sequence complementarity and even more preferably comprise 95% sequence complementarity to the target region within the target nucleic acid sequence to which they are targeted. For example, an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, an antisense compound which is 18 nucleobases in length having 4 (four) noncomplementary nucleobases which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid and would thus fall within the scope of the present invention. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656).

[0028] B. Compounds of the Invention

[0029] According to the present invention, compounds include antisense oligomeric compounds, antisense oligonucleotides, ribozymes, external guide sequence (EGS) oligonucleotides, alternate splicers, primers, probes, and other oligomeric compounds which hybridize to at least a portion of the target nucleic acid. As such, these compounds may be introduced in the form of single-stranded, double-stranded, circular or hairpin oligomeric compounds and may contain structural elements such as internal or terminal bulges or loops. Once introduced to a system, the compounds of the invention may elicit the action of one or more enzymes or structural proteins to effect modification of the target nucleic acid. One non-limiting example of such an enzyme is RNAse H, a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are “DNA-like” elicit RNAse H. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide-mediated inhibition of gene expression. Similar roles have been postulated for other ribonucleases such as those in the RNase III and ribonuclease L family of enzymes.

[0030] While the preferred form of antisense compound is a single-stranded antisense oligonucleotide, in many species the introduction of double-stranded structures, such as double-stranded RNA (dsRNA) molecules, has been shown to induce potent and specific antisense-mediated reduction of the function of a gene or its associated gene products. This phenomenon occurs in both plants and animals and is believed to have an evolutionary connection to viral defense and transposon silencing.

[0031] The first evidence that dsRNA could lead to gene silencing in animals came in 1995 from work in the nematode, Caenorhabditis elegans (Guo and Kempheus, Cell, 1995, 81, 611-620). Montgomery et al. have shown that the primary interference effects of dsRNA are posttranscriptional (Montgomery et al., Proc. Natl. Acad. Sci. USA, 1998, 95, 15502-15507). The posttranscriptional antisense mechanism defined in Caenorhabditis elegans resulting from exposure to double-stranded RNA (dsRNA) has since been designated RNA interference (RNAi). This term has been generalized to mean antisense-mediated gene silencing involving the introduction of dsRNA leading to the sequence-specific reduction of endogenous targeted mRNA levels (Fire et al., Nature, 1998, 391, 806-811). Recently, it has been shown that it is, in fact, the single-stranded RNA oligomers of antisense polarity of the dsRNAs which are the potent inducers of RNAi (Tijsterman et al., Science, 2002, 295, 694-697).

[0032] In the context of this invention, the term “oligomeric compound” refers to a polymer or oligomer comprising a plurality of monomeric units. In the context of this invention, the term “oligonucleotide” refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics, chimeras, analogs and homologs thereof. This term includes oligonucleotides composed of naturally occurring nucleobases, sugars and covalent internucleoside (backbone) linkages as well as oligonucleotides having non-naturally occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred rover native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for a target nucleic acid and increased stability in the presence of nucleases.

[0033] While oligonucleotides are a preferred form of the compounds of this invention, the present invention comprehends other families of compounds as well, including but not limited to oligonucleotide analogs and mimetics such as those described herein.

[0034] The compounds in accordance with this invention preferably comprise from about 8 to about 80 nucleobases (i.e. from about 8 to about 80 linked nucleosides). One of ordinary skill in the art will appreciate that the invention embodies compounds of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 nucleobases in length.

[0035] In one preferred embodiment, the compounds of the invention are 12 to 50 nucleobases in length. One having ordinary skill in the art will appreciate that this embodies compounds of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleobases in length.

[0036] In another preferred embodiment, the compounds of the invention are 15 to 30 nucleobases in length. One having ordinary skill in the art will appreciate that this embodies compounds of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length.

[0037] Particularly preferred compounds are oligonucleotides from about 12 to about 50 nucleobases, even more preferably those comprising from about 15 to about 30 nucleobases.

[0038] Antisense compounds 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative antisense compounds are considered to be suitable antisense compounds as well.

[0039] Exemplary preferred antisense compounds include oligonucleotide sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same oligonucleotide beginning immediately upstream of the 5′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the oligonucleotide contains about 8 to about 80 nucleobases). Similarly preferred antisense compounds are represented by oligonucleotide sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same oligonucleotide beginning immediately downstream of the 3′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the oligonucleotide contains about 8 to about 80 nucleobases). One having skill in the art armed with the preferred antisense compounds illustrated herein will be able, without undue experimentation, to identify further preferred antisense compounds.

[0040] C. Targets of the Invention

[0041] “Targeting” an antisense compound to a particular nucleic acid molecule, in the context of this invention, can be:a multistep process. The process usually begins with the identification of a target nucleic acid whose function is to be modulated. This target nucleic acid may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target nucleic acid encodes PTPN13.

[0042] The targeting process usually also includes determination of at least one target region, segment, or site within the target nucleic acid for the antisense interaction to occur such that the desired effect, e.g., modulation of expression, will result. Within the context of the present invention, the term “region” is defined as a portion of the target nucleic acid having at least one identifiable structure, function, or characteristic. Within regions of target nucleic acids are segments. “Segments” are defined as smaller or sub-portions of regions within a target nucleic acid. “Sites,” as used in the present invention, are defined as positions within a target nucleic acid.

[0043] Since, as is known in the art, the translation initiation codon is typically 5′-AUG (in transcribed mRNA molecules; 5′-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the “AUG codon,” the “start codon” or the “AUG start codon”. A minority of genes have a translation initiation codon having the RNA sequence 5′-GUG, 5′-UUG or 5′-CUG, and 5′-AUA, 5′-ACG and 5′-CUG have been shown to function in vivo. Thus, the terms “translation initiation codon” and “start codon” can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, “start codon” and “translation initiation codon” refer to the codon or codons that are used in vivo to initiate translation of an mRNA transcribed from a gene encoding PTPN13, regardless of the sequence(s) of such codons. It is also known in the art that a translation termination codon (or “stop codon”) of a gene may have one of three sequences, i.e., 5′-UAA, 5′-UAG and 5′-UGA (the corresponding DNA sequences are 5′-TAA, 5′-TAG and 5′-TGA, respectively).

[0044] The terms “start codon region” and “translation initiation codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′or 3′) from a translation initiation codon. Similarly, the terms “stop codon region” and “translation termination codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′ or 3′) from a translation termination codon. Consequently, the “start codon region” (or “translation initiation codon region”) and the “stop codon region” (or “translation termination codon region”) are all regions which may be targeted effectively with the antisense compounds of the present invention.

[0045] The open reading frame (ORF) or “coding region,” which is known in the art to refer to the region between the translation initiation codon and the translation termination codon, is also a region which may be targeted effectively. Within the context of the present invention, a preferred region is the intragenic region encompassing the translation initiation or termination codon of the open reading frame (ORF) of a gene.

[0046] Other target regions include the 5′ untranslated region (5′UTR), known in the art to refer to the portion of an mRNA in the 5′ direction from the translation initiation codon, and thus including nucleotides between the 5′ cap site and the translation initiation codon of an mRNA (or corresponding nucleotides on the gene), and the 3′ untranslated region (3′UTR), known in the art to refer to the portion of an mRNA in the 3′ direction from the translation termination codon, and thus including nucleotides between the translation termination codon and 3′ end of an mRNA (or corresponding nucleotides on the gene). The 5′ cap site of an mRNA comprises an N7-methylated guanosine residue joined to the 5′-most residue of the mRNA via a 5′-5′ triphosphate linkage. The 5′ cap region of an mRNA is considered to include the 5′ cap structure itself as well as the first 50 nucleotides adjacent to the cap site. It is also preferred to target the 5′ cap region.

[0047] Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions, known as “introns,” which are excised from a transcript before it is translated. The remaining (and therefore translated) regions are known as “exons” and are spliced together to form a continuous mRNA sequence. Targeting splice sites, i.e., intron-exon junctions or exon-intron junctions, may also be particularly useful in situations where aberrant splicing is implicated in disease, or where an overproduction of a particular splice product is implicated in disease. Aberrant fusion junctions due to rearrangements or deletions are also preferred target sites. mRNA transcripts produced via the process of splicing of two (or more) mRNAs from different gene sources are known as “fusion transcripts”. It is also known that introns can be effectively targeted using antisense compounds targeted to, for example, DNA or pre-mRNA.

[0048] It is also known in the art that alternative RNA transcripts can be produced from the same genomic region of DNA. These alternative transcripts are generally known as “variants”. More specifically, “pre-mRNA variants” are transcripts produced from the same genomic DNA that differ from other transcripts produced from the same genomic DNA in either their start or stop position and contain both intronic and exonic sequence.

[0049] Upon excision of one or more exon or intron regions, or portions thereof during splicing, pre-mRNA variants produce smaller “mRNA variants”. Consequently, mRNA variants are processed pre-mRNA variants and each unique pre-mRNA variant must always produce a unique mRNA variant as a result of splicing. These mRNA variants are also known as “alternative splice variants”. If no splicing of the pre-mRNA variant occurs then the pre-mRNA variant is identical to the mRNA variant.

[0050] It is also known in the art that variants can be produced through the use of alternative signals to start or stop transcription and that pre-mRNAs and mRNAs can possess more that one start codon or stop codon. Variants that originate from a pre-mRNA or mRNA that use alternative start codons are known as “alternative start variants” of that pre-mRNA or mRNA. Those transcripts that use an alternative stop codon are known as “alternative stop variants” of that pre-mRNA or mRNA. One specific type of alternative stop variant is the “polyA variant” in which the multiple transcripts produced result from the alternative selection of one of the “polyA stop signals” by the transcription machinery, thereby producing transcripts that terminate at unique polyA sites. Within the context of the invention, the types of variants described herein are also preferred target nucleic acids.

[0051] The locations on the target nucleic acid to which the preferred antisense compounds hybridize are hereinbelow referred to as “preferred target segments.” As used herein the term “preferred target segment” is defined as at least an 8-nucleobase portion of a target region to which an active antisense compound is targeted. While not wishing to be bound by theory, it is presently believed that these target segments represent portions of the target nucleic acid which are accessible for hybridization.

[0052] While the specific sequences of certain preferred target segments are set forth herein, one of skill in the art will recognize that these serve to illustrate and describe particular embodiments within the scope of the present invention. Additional preferred target segments may be identified by one having ordinary skill.

[0053] Target segments 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative preferred target segments are considered to be suitable for targeting as well.

[0054] Target segments can include DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred target segments (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately upstream of the 5′-terminus of the target segment and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). Similarly preferred target segments are represented by DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred target segments (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately downstream of the 3′-terminus of the target segment and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). One having skill in the art armed with the preferred target segments illustrated herein will be able, without undue experimentation, to identify further preferred target segments.

[0055] Once one or more target regions, segments or sites have been identified, antisense compounds are chosen which are sufficiently complementary to the target, i.e., hybridize sufficiently well and with sufficient specificity, to give the desired effect.

[0056] D. Screening and Target Validation

[0057] In a further embodiment, the “preferred target segments” identified herein may be employed in a screen for additional compounds that modulate the expression of PTPN13. “Modulators” are those compounds that decrease or increase the expression of a nucleic acid molecule encoding PTPN13 and which comprise at least an 8-nucleobase portion which is complementary to a preferred target segment. The screening method comprises the steps of contacting a preferred target segment of a nucleic acid molecule encoding PTPN13 with one or more candidate modulators, and selecting for one or more candidate modulators which decrease or increase the expression of a nucleic acid molecule encoding PTPN13. Once it is shown that the candidate modulator or modulators are capable of modulating (e.g. either decreasing or increasing) the expression of a nucleic acid molecule encoding PTPN13, the modulator may then be employed in further investigative studies of the function of PTPN13, or for use as a research, diagnostic, or therapeutic agent in accordance with the present invention.

[0058] The preferred target segments of the present invention may be also be combined with their respective complementary antisense compounds of the present invention to form stabilized double-stranded (duplexed) oligonucleotides.

[0059] Such double stranded oligonucleotide moieties have been shown in the art to modulate target expression and regulate translation as well as RNA processsing via an antisense mechanism. Moreover, the double-stranded moieties may be subject to chemical modifications (Fire et al., Nature, 1998, 391, 806-811; Timmons and Fire, Nature 1998, 395, 854; Timmons et al., Gene, 2001, 263, 103-112; Tabara et al., Science, 1998, 282, 430-431; Montgomery et al., Proc. Natl. Acad. Sci. USA, 1998, 95, 15502-15507; Tuschl et al., Genes Dev., 1999, 13, 3191-3197; Elbashir et al., Nature, 2001, 411, 494-498; Elbashir et al., Genes Dev. 2001, 15, 188-200). For example, such double-stranded moieties have been shown to inhibit the target by the classical hybridization of antisense strand of the duplex to the target, thereby triggering enzymatic degradation of the target (Tijsterman et al., Science, 2002, 295, 694-697).

[0060] The compounds of the present invention can also be applied in the areas of drug discovery and target validation. The present invention comprehends the use of the compounds and preferred target segments identified herein in drug discovery efforts to elucidate relationships that exist between PTPN13 and a disease state, phenotype, or condition. These methods include detecting or modulating PTPN13 comprising contacting a sample, tissue, cell, or organism with the compounds of the present invention, measuring the nucleic acid or protein level of PTPN13 and/or a related phenotypic or chemical endpoint at some time after treatment, and optionally comparing the measured value to a non-treated sample or sample treated with a further compound of the invention. These methods can also be performed in parallel or in combination with other experiments to determine the function of unknown genes for the process of target validation or to determine the validity of a particular gene product as a target for treatment or prevention of a particular disease, condition, or phenotype.

[0061] E. Kits, Research Reagents, Diagnostics, and Therapeutics

[0062] The compounds of the present invention can be utilized for diagnostics, therapeutics, prophylaxis and as research reagents and kits. Furthermore, antisense oligonucleotides, which are able to inhibit gene expression with exquisite specificity, are often used by those of ordinary skill to elucidate the function of particular genes or to distinguish between functions of various members of a biological pathway.

[0063] For use in kits and diagnostics, the compounds of the present invention, either alone or in combination with other compounds or therapeutics, can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of a portion or the entire complement of genes expressed within cells and tissues.

[0064] As one nonlimiting example, expression patterns within cells or tissues treated with one or more antisense compounds are compared to control cells or tissues not treated with antisense compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined. These analyses can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.

[0065] Examples of methods of gene expression analysis known in the art include DNA arrays or microarrays (Brazma and Vilo, FEBS Lett., 2000, 480, 17-24; Celis, et al., FEBS Lett., 2000, 480, 2-16), SAGE (serial analysis of gene expression)(Madden, et al., Drug Discov. Today, 2000, 5, 415-425), READS (restriction enzyme amplification of digested cDNAs) (Prashar and Weissman, Methods Enzymol., 1999, 303, 258-72), TOGA (total gene expression analysis) (Sutcliffe, et al., Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 1976-81), protein arrays and proteomics (Celis, et al., FEBS Lett., 2000, 480, 2-16; Jungblut, et al., Electrophoresis, 1999, 20, 2100-10), expressed sequence tag (EST) sequencing (Celis, et al., FEBS Lett., 2000, 480, 2-16; Larsson, et al., J. Biotechnol., 2000, 80, 143-57), subtractive RNA fingerprinting (SuRF) (Fuchs, et al., Anal. Biochem., 2000, 286, 91-98; Larson, et al., Cytometry, 2000, 41, 203-208), subtractive cloning, differential display (DD) (Jurecic and Belmont, Curr. Opin. Microbiol., 2000, 3, 316-21), comparative genomic hybridization (Carulli, et al., J. Cell Biochem. Suppl., 1998, 31, 286-96), FISH (fluorescent in situ hybridization) techniques (Going and Gusterson, Eur. J. Cancer, 1999, 35, 1895-904) and mass spectrometry methods (To, Comb. Chem. High Throughput Screen, 2000, 3, 235-41).

[0066] The compounds of the invention are useful for research and diagnostics, because these compounds hybridize to nucleic acids encoding PTPN13. For example, oligonucleotides that are shown to hybridize with such efficiency and under such conditions as disclosed herein as to be effective PTPN13 inhibitors will also be effective primers or probes under conditions favoring gene amplification or detection, respectively. These primers and probes are useful in methods requiring the specific detection of nucleic acid molecules encoding PTPN13 and in the amplification of said nucleic acid molecules for detection or for use in further studies of PTPN13. Hybridization of the antisense oligonucleotides, particularly the primers and probes, of the invention with a nucleic acid encoding PTPN13 can be detected by means known in the art. Such means may include conjugation of an enzyme to the oligonucleotide, radiolabelling of the oligonucleotide or any other suitable detection means. Kits using such detection means for detecting the level of PTPN13 in a sample may also be prepared.

[0067] The specificity and sensitivity of antisense is also harnessed by those of skill in the art for therapeutic uses. Antisense compounds have been employed as therapeutic moieties in the treatment of disease states in animals, including humans. Antisense oligonucleotide drugs, including ribozymes, have been safely and effectively administered to humans and numerous clinical trials are presently underway. It is thus established that antisense compounds can be useful therapeutic modalities that can be configured to be useful in treatment regimes for the treatment of cells, tissues and animals, especially humans.

[0068] For therapeutics, an animal, preferably a human, suspected of having a disease or disorder which can be treated by modulating the expression of PTPN13 is treated by administering antisense compounds in accordance with this invention. For example, in one non-limiting embodiment, the methods comprise the step of administering to the animal in need of treatment, a therapeutically effective amount of a PTPN13 inhibitor. The PTPN13 inhibitors of the present invention effectively inhibit the activity of the PTPN13 protein or inhibit the expression of the PTPN13 protein. In one embodiment, the activity or expression of PTPN13 in an animal is inhibited by about 10%. Preferably, the activity oriexpression of PTPN13 in an animal is inhibited by about 30%. More preferably, the activity or expression of PTPN13 in an animal is inhibited by 50% or more.

[0069] For example, the reduction of the expression of PTPN13 may be measured in serum, adipose tissue, liver or any other body fluid, tissue or organ of the animal. Preferably, the cells contained within said fluids, tissues or organs being analyzed contain a nucleic acid molecule encoding PTPN13 protein and/or the PTPN13 protein itself.

[0070] The compounds of the invention can be utilized in pharmaceutical compositions by adding an effective amount of a compound to a suitable pharmaceutically acceptable diluent or carrier. Use of the compounds and methods of the invention may also be useful prophylactically.

[0071] F. Modifications

[0072] As is known in the art, a nucleoside is a base-sugar combination. The base portion of the nucleoside is normally a heterocyclic base. The two most common classes of such heterocyclic bases are the purines and the pyrimidines. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to either the 2′, 3′ or 5′ hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. In turn, the respective ends of this linear polymeric compound can be further joined to form a circular compound, however, linear compounds are generally preferred. In addition, linear compounds may have internal nucleobase complementarity and may therefore fold in a manner as to produce a fully or partially double-stranded compound. Within oligonucleotides, the phosphate groups are commonly referred to as forming the internucleoside backbone of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3′ to 5′ phosphodiester linkage.

[0073] Modified Internucleoside Linkages (Backbones)

[0074] Specific examples of preferred antisense compounds useful in this invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. As defined in this specification, oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides.

[0075] Preferred modified oligonucleotide backbones containing a phosphorus atom therein include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates, 5′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, selenophosphates and borano-phosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein one or more internucleotide linkages is a 3′ to 3′, 5′ to 5′ or 2′ to 2′ linkage. Preferred oligonucleotides having inverted polarity comprise a single 3′ to 3′ linkage at the 3′-most internucleotide linkage i.e. a single inverted nucleoside residue which may be abasic (the nucleobase is missing or has a hydroxyl group in place thereof). Various salts, mixed salts and free acid forms are also included.

[0076] Representative United States patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos.: 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,194,599; 5,565,555; 5,527,899; 5,721,218; 5,672,697 and 5,625,050, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.

[0077] Preferred modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; riboacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH₂ component parts.

[0078] Representative United States patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos.: 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; 5,792,608; 5,646,269 and 5,677,439, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.

[0079] Modified sugar and intern ucleoside linkages—Mimetics

[0080] In other preferred oligonucleotide mimetics, both the sugar and the internucleoside linkage (i.e. the backbone), of the nucleotide units are replaced with novel groups. The nucleobase units are maintained for hybridization with an appropriate target nucleic acid. One such compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos.: 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al., Science, 1991, 254, 1497-1500.

[0081] Preferred embodiments of the invention are oligonucleotides with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular —CH₂—NH—O—CH₂—, —CH₂—N(CH₃)—O—CH₂— [known as a methylene (methylimino) or MMI backbone], —CH₂—O—N(CH₃)—CH₂—, —CH₂— N(CH₃)—N(CH₃)—CH₂— and —O—N(CH₃)—CH₂—CH₂— [wherein the native phosphodiester backbone is represented as —O—P—O—CH₂—] of the above referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above referenced U.S. Pat. No. 5,602,240. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506.

[0082] Modified sugars

[0083] Modified oligonucleotides may also contain one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following at the 2′ position: OH; F; O—, S-, or N-alkyl; O-, S-, or N-alkenyl; O—, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C₁ to C₁₀ alkyl or C₂ to C₁₀ alkenyl and alkynyl. Particularly preferred are O[(CH₂)_(n)O]_(m)CH₃, O(CH₂)_(n)OCH₃, O(CH₂)_(n)NH₂, O(CH₂)_(n)CH₃, O(CH₂)_(n)ONH₂, and O(CH₂)_(n)ON[(CH₂)_(n)CH₃]₂, where n and m are from 1 to about 10. Other preferred oligonucleotides comprise one of the following at the 2′ position: C₁ to C₁₀ lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃, OCN, Cl, Br, CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2′-methoxyethoxy (2′-O—CH₂CH₂OCH₃, also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78, 486-504) i.e., an alkoxyalkoxy group. A further preferred modification includes 2′-dimethylaminooxyethoxy, i.e., a O(CH₂)₂ON(CH₃)₂ group, also known as 2′-DMAOE, as described in examples hereinbelow, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethyl-amino-ethoxy-ethyl or 2′-DMAEOE), i.e., 2′-O—CH₂-O-CH₂—N(CH₃)₂, also described in examples hereinbelow.

[0084] Other preferred modifications include 2′-methoxy (2′-O—CH₃), 2′-aminopropoxy (2′-OCH₂CH₂CH₂NH₂), 2′-allyl (2′-CH₂—CH═CH₂), 2′-O-allyl (2′-O—CH₂—CH═CH₂) and 2′-fluoro (2′-F). The 2′-modification may be in the arabino (up) position or ribo (down) position. A preferred 2′-arabino modification is 2′-F. Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides and the 5′ position of 5′ terminal nucleotide. Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos.: 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,792,747; and 5,700,920, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.

[0085] A further preferred modification of the sugar includes Locked Nucleic Acids (LNAs) in which the 2′-hydroxyl group is linked to the 3′ or 4′ carbon atom of the sugar ring, thereby forming a bicyclic sugar moiety. The linkage is preferably a methylene (—CH₂—)_(n) group bridging the 2′ oxygen atom and the 4′ carbon atom wherein n is 1 or 2. LNAs and preparation thereof are described in WO 98/39352 and WO 99/14226.

[0086] Natural and Modified Nucleobases

[0087] Oligonucleotides may also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (—C≡—C—CH₃) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further modified nucleobases include tricyclic pyrimidines such as phenoxazine cytidine (1H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), phenothiazine cytidine (1H-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps such as a substituted phenoxazine cytidine (e.g. 9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), carbazole cytidine (2H-pyrimido[4,5-b]indol-2-one), pyridoindole cytidine (H-pyrido[3′,2′:4,5]pyrrolo[2,3-d]pyrimidin-2-one). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. I., ed. John Wiley & Sons, 1990, those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y.S., Chapter 15, Antisense Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B., ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. and are presently preferred base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications.

[0088] Representative United States patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos.: 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,645,985; 5,830,653; 5,763,588; 6,005,096; and 5,681,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, which is commonly owned with the instant application and also herein incorporated by reference.

[0089] Conjugates

[0090] Another modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. These moieties or conjugates can include conjugate groups covalently bound to functional groups such as primary or secondary hydroxyl groups. Conjugate groups of the invention include intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligomers, and groups that enhance the pharmacokinetic properties of oligomers. Typical conjugate groups include cholesterols, lipids, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. Groups that enhance the pharmacodynamic properties, in the context of this invention, include groups that improve uptake, enhance resistance to degradation, and/or strengthen sequence-specific hybridization with the target nucleic acid. Groups that enhance the pharmacokinetic properties, in the context of this invention, include groups that improve uptake, distribution, metabolism or excretion of the compounds of the present invention. Representative conjugate groups are disclosed in International Patent Application PCT/US92/09196, filed Oct. 23, 1992, and U.S. Pat. No. 6,287,860, the entire disclosure of which are incorporated herein by reference. Conjugate moieties include but are not limited to lipid moieties such as a cholesterol moiety, cholic acid, a thioether, e.g., hexyl-S-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate, a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety. Oligonucleotides of the invention may also be conjugated to active drug substances, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indomethicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. Oligonucleotide-drug conjugates and their preparation are described in U.S. application Ser. No. 09/334,130 (filed Jun. 15, 1999) which is incorporated herein by reference in its entirety.

[0091] Representative United States patents that teach the preparation of such oligonucleotide conjugates include, but are not limited to, U.S. Pat. Nos.: 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044,; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference.

[0092] Chimeric compounds

[0093] It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide.

[0094] The present invention also includes antisense compounds which are chimeric compounds. “Chimeric” antisense compounds or “chimeras,” in the context of this invention, are antisense compounds, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, increased stability and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNAse H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide-mediated inhibition of gene expression. The cleavage of RNA:RNA hybrids can, in like fashion, be accomplished through the actions of endoribonucleases, such as RNAseL which cleaves both cellular and viral RNA. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art.

[0095] Chimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers. Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Pat. Nos.: 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.

[0096] G. Formulations

[0097] The compounds of the invention may also be admixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, receptor-targeted molecules, oral, rectal, topical or other formulations, for assisting in uptake, distribution and/or absorption. Representative United States patents that teach the preparation of such uptake, distribution and/or absorption-assisting formulations include, but are not limited to, U.S. Pat. Nos.: 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291; 5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330; 4,534,899; 5,013,556; 5,108,921; 5,213,804; 5,227,170; 5,264,221; 5,356,633; 5,395,619; 5,416,016; 5,417,978; 5,462,854; 5,469,854; 5,512,295; 5,527,528; 5,534,259; 5,543,152; 5,556,948; 5,580,575; and 5,595,756, each of which is herein incorporated by reference.

[0098] The antisense compounds of the invention encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to prodrugs and pharmaceutically acceptable salts of the compounds of the invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents.

[0099] The term “prodrug” indicates a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions. In particular, prodrug versions of the oligonucleotides of the invention are prepared as SATE [(S-acetyl-2-thioethyl) phosphate] derivatives according to the methods disclosed in WO 93/24510 to Gosselin et al., published Dec. 9, 1993 or in WO 94/26764 and U.S. Pat. No. 5,770,713 to Imbach et al.

[0100] The term “pharmaceutically acceptable salts” refers to physiologically and pharmaceutically acceptable salts of the compounds of the invention: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto. For oligonucleotides, preferred examples of pharmaceutically acceptable salts and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0101] The present invention also includes pharmaceutical compositions and formulations which include the antisense compounds of the invention. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Oligonucleotides with at least one 2′-O-methoxyethyl modification are believed to be particularly useful for oral administration. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.

[0102] The pharmaceutical formulations of the present invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0103] The compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.

[0104] Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, foams and liposome-containing formulations. The pharmaceutical compositions and formulations of the present invention may comprise one or more penetration enhancers, carriers, excipients or other active or inactive ingredients.

[0105] Emulsions are typically heterogenous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 μm in diameter. Emulsions may contain additional components in addition to the dispersed phases, and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Microemulsions are included as an embodiment of the present invention. Emulsions and their uses are well known in the art and are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0106] Formulations of the present invention include liposomal formulations. As used in the present invention, the term “liposome” means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers. Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior that contains the composition to be delivered. Cationic liposomes are positively charged liposomes which are believed to interact with negatively charged DNA molecules to form a stable complex. Liposomes that are pH-sensitive or negatively-charged are believed to entrap DNA rather than complex with it. Both cationic and noncationic liposomes have been used to deliver DNA to cells.

[0107] Liposomes also include “sterically stabilized” liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome comprises one or more glycolipids or is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. Liposomes and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0108] The pharmaceutical formulations and compositions of the present invention may also include surfactants. The use of surfactants in drug products, formulations and in emulsions is well known in the art. Surfactants and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0109] In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly oligonucleotides. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs. Penetration enhancers may be classified as belonging to one of five broad categories, i.e., surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants. Penetration enhancers and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0110] One of skill in the art will recognize that formulations are routinely designed according to their intended use, i.e. route of administration.

[0111] Preferred formulations for topical administration include those in which the oligonucleotides of the invention are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Preferred lipids and liposomes include neutral (e.g. dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearolyphosphatidyl choline) negative (e.g. dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g. dioleoyltetramethylaminopropyl DOTAP and dioleoylphosphatidyl ethanolamine DOTMA).

[0112] For topical or other administration, oligonucleotides of the invention may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, oligonucleotides may be complexed to lipids, in particular to cationic lipids. Preferred fatty acids and esters, pharmaceutically acceptable salts thereof, and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety. Topical formulations are described in detail in U.S. patent application Ser. No. 09/315,298 filed on May 20, 1999, which is incorporated herein by reference in its entirety.

[0113] Compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable. Preferred oral formulations are those in which oligonucleotides of the invention are administered in conjunction with one or more penetration enhancers surfactants and chelators. Preferred surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Preferred bile acids/salts and fatty acids and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety. Also preferred are combinations of penetration enhancers, for example, fatty acids/salts in combination with bile acids/salts. A particularly preferred combination is the sodium salt of lauric acid, capric acid and UDCA. Further penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. Oligonucleotides of the invention may be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. Oligonucleotide complexing agents and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety. Oral formulations for oligonucleotides and their preparation are described in detail in U.S. application Ser. Nos. 09/108,673 (filed Jul. 1, 1998), 09/315,298 (filed May 20, 1999) and 10/071,822, filed Feb. 8, 2002, each of which is incorporated herein by reference in their entirety.

[0114] Compositions and formulations for parenteral, intra-thecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.

[0115] Certain embodiments of the invention provide pharmaceutical compositions containing one or more oligomeric compounds and one or more other chemotherapeutic agents which function by a non-antisense mechanism. Examples of such chemotherapeutic agents include but are not limited to cancer chemotherapeutic drugs such as daunorubicin, daunomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, esorubicin, bleomycin, mafosfamide, ifosfamide, cytosine ara-binoside, bis-chloroethylnitrosurea, busulfan, mitomycin C, actinomycin D, mithramycin, prednisone, hydroxyprogesterone, testosterone, tamoxifen, dacarbazine, procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil, methylcyclohexylnitrosurea, nitrogen mustards, melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-azacytidine, hydroxyurea, deoxyco-formycin, 4-hydroxyperoxycyclophosphoramide, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5-FUdR), methotrexate (MTX), colchicine, taxol, vincristine, vinblastine, etoposide (VP-16), trimetrexate, irinotecan, topotecan, gemcitabine, teniposide, cisplatin and diethylstilbestrol (DES). When used with the compounds of the invention, such chemotherapeutic agents may be used individually (e.g., 5-FU and oligonucleotide), sequentially (e.g., 5-FU and oligonucleotide for a period of time followed by MTX and oligonucleotide), or in combination with one or more other such chemotherapeutic agents (e.g., 5-FU, MTX and oligonucleotide, or 5-FU, radiotherapy and oligonucleotide). Anti-inflammatory drugs, including but not limited to nonsteroidal anti-inflammatory drugs and corticosteroids, and antiviral drugs, including but not limited to ribivirin, vidarabine, acyclovir and ganciclovir, may also be combined in compositions of the invention. Combinations of antisense compounds and other non-antisense drugs are also within the scope of this invention. Two or more combined compounds may be used together or sequentially.

[0116] In another related embodiment, compositions of the invention may contain one or more antisense compounds, particularly oligonucleotides, targeted to a first nucleic acid and one or more additional antisense compounds targeted to a second nucleic acid target. Alternatively, compositions of the invention may contain two or more antisense compounds targeted to different regions of the same nucleic acid target. Numerous examples of antisense compounds are known in the art. Two or more combined compounds may be used together or sequentially.

[0117] H. Dosing

[0118] The formulation of therapeutic compositions and their subsequent administration (dosing) is believed to be within the skill of those in the art. Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual oligonucleotides, and can generally be estimated based on EC₅₀s found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 ug to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the oligonucleotide is administered in maintenance doses, ranging from 0.01 ug to 100 g per kg of body weight, once or more daily, to once every 20 years.

[0119] While the present invention has been described with specificity in accordance with certain of its preferred embodiments, the following examples serve only to illustrate the invention and are not intended to limit the same.

EXAMPLES Example 1

[0120] Synthesis of Nucleoside Phosphoramidites

[0121] The following compounds, including amidites and their intermediates were prepared as described in U.S. Pat. No. 6,426,220 and published PCT WO 02/36743; 5′-O-Dimethoxytrityl-thymdine intermediate for 5-methyl dC amidite, 5′-O—Dimethoxytrityl-2′-deoxy-5-methylcytidine intermediate for 5-methyl-dC amidite, 5′-O—Dimethoxytrityl-2′-deoxy-N4-benzoyl-5-methylcytidine penultimate intermediate for 5-methyl dC amidite, [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N⁴-benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl—N,N-diisopropylphosphoramidite (5-methyl dC amidite), 2′-Fluorodeoxyadenosine, 2′-Fluorodeoxyguanosine, 2′-Fluorouridine, 2′-Fluorodeoxycytidine, 2′-O-(2-Methoxyethyl) modified amidites, 2′-O-(2-methoxyethyl)-5-methyluridine intermediate, 5′-O—DMT-2′-O-(2-methoxyethyl)-5-methyluridine penultimate intermediate, [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-5-methyluridin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE T amidite), 5′-O-Dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methylcytidine intermediate, 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-N⁴-benzoyl-5-methyl-cytidine penultimate intermediate, [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)—N-benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE 5-Me—C amidite), [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N′-benzoyladenosin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE A amdite), [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁴-N-isobutyrylguanosin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE G amidite), 2′-O-(Aminooxyethyl) nucleoside amidites and 2′-O-(dimethylamino-oxyethyl) nucleoside amidites, 2′-(Dimethylaminooxyethoxy) nucleoside amidites, 5′-O-tert-Butyldiphenylsilyl-O²-2¹-anhydro-5-methyluridine , 5′-O-tert-Butyldiphenylsilyl-2′-O-(2-hydroxyethyl)-5-methyluridine, 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine, 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy)ethyl]-5-methyluridine, 5′-O-tert-Butyldiphenylsilyl-2′-O-[N,N dimethylaminooxyethyl]-5-methyluridine, 2′-O-(dimethylaminooxyethyl)-5-methyluridine, 5′-O—DMT-2′-O-(dimethylaminooxyethyl)-5-methyluridine, 5′-O-DMT-2′-O-(2-N,N-dimethylaminooxyethyl)-5-methyluridine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite], 2′-(Aminooxyethoxy) nucleoside amidites, N2-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite], 2′-dimethylaminoethoxyethoxy (2′-DMAEOE) nucleoside amidites, 2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl]-5-methyl uridine, 5′-O-dimethoxytrityl-2′-O-[2(2—N,N-dimethylaminoethoxy)-ethyl)]-5-methyl uridine and 5′-O—Dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)-ethyl)]-5-methyl uridine-3′-O-cyanoethyl-N,N-diisopropyl)phosphoramidite.

Example 2

[0122] Oligonucleotide and oligonucleoside synthesis

[0123] The antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives.

[0124] Oligonucleotides: Unsubstituted and substituted phosphodiester (P═O) oligonucleotides are synthesized on an automated DNA synthesizer (Applied Biosystems model 394) using standard phosphoramidite chemistry with oxidation by iodine.

[0125] Phosphorothioates (P═S) are synthesized similar to phosphodiester oligonucleotides with the following exceptions: thiation was effected by utilizing a 10% w/v solution of 3,H-1,2-benzodithiole-3-one 1,1-dioxide in acetonitrile for the oxidation of the phosphite linkages. The thiation reaction step time was increased to 180 sec and preceded by the normal capping step. After cleavage from the CPG column and deblocking in concentrated ammonium hydroxide at 55° C. (12-16 hr), the oligonucleotides were recovered by precipitating with >3 volumes of ethanol from a 1 M NH₄OAc solution. Phosphinate oligonucleotides are prepared as described in U.S. Pat. No. 5,508,270, herein incorporated by reference.

[0126] Alkyl phosphonate oligonucleotides are prepared as described in U.S. Pat. No. 4,469,863, herein incorporated by reference.

[0127] 3,-Deoxy-3′-methylene phosphonate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,610,289 or 5,625,050, herein incorporated by reference.

[0128] Phosphoramidite oligonucleotides are prepared as described in U.S. Pat. No. 5,256,775 or U.S. Pat. No. 5,366,878, herein incorporated by reference.

[0129] Alkylphosphonothioate oligonucleotides are prepared as described in published PCT applications PCT/US94/00902 and PCT/US93/06976 (published as WO 94/17093 and WO 94/02499, respectively), herein incorporated by reference.

[0130] 3′-Deoxy-3′-amino phosphoramidate oligonucleotides are prepared as described in U.S. Pat. No. 5,476,925, herein incorporated by reference.

[0131] Phosphotriester oligonucleotides are prepared as described in U.S. Pat. No. 5,023,243, herein incorporated by reference.

[0132] Borano phosphate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,130,302 and 5,177,198, both herein incorporated by reference.

[0133] Oligonucleosides: Methylenemethylimino linked oligonucleosides, also identified as MMI linked oligonucleosides, methylenedimethylhydrazo linked oligonucleosides, also identified as MDH linked oligonucleosides, and methylenecarbonylamino linked oligonucleosides, also identified as amide-3 linked oligonucleosides, and methyleneaminocarbonyl linked oligo-nucleosides, also identified as amide-4 linked oligonucleotide sides, as well as mixed backbone compounds having, for instance, alternating MMI and P═O or P═S linkages are prepared as described in U.S. Pat. Nos. 5,378,825, 5,386,023, 5,489,677, 5,602,240 and 5,610,289, all of which are herein incorporated by reference.

[0134] Formacetal and thioformacetal linked oligonucleosides are prepared as described in U.S. Pat. Nos. 5,264,562 and 5,264,564, herein incorporated by reference.

[0135] Ethylene oxide linked oligonucleosides are prepared as described in U.S. Pat. No. 5,223,618, herein incorporated by reference.

Example 3

[0136] RNA Synthesis

[0137] In general, RNA synthesis chemistry is based on the selective incorporation of various protecting groups at strategic intermediary reactions. Although one of ordinary skill in the art will understand the use of protecting groups in organic synthesis, a useful class of protecting groups includes silyl ethers. In particular bulky silyl ethers are used to protect the 5′-hydroxyl in combination with an acid-labile orthoester protecting group on the 2′-hydroxyl. This set of protecting groups is then used with standard solid-phase synthesis technology. It is important to lastly remove the acid labile orthoester protecting group after all other synthetic steps. Moreover, the early use of the silyl protecting groups during synthesis ensures facile removal when desired, without undesired deprotection of 2′ hydroxyl.

[0138] Following this procedure for the sequential protection of the 5′-hydroxyl in combination with protection of the 2′-hydroxyl by protecting groups that are differentially removed and are differentially chemically labile, RNA oligonucleotides were synthesized.

[0139] RNA oligonucleotides are synthesized in a stepwise fashion. Each nucleotide is added sequentially (3′- to 5′-direction) to a solid support-bound oligonucleotide. The first nucleoside at the 3′-end of the chain is covalently attached to a solid support. The nucleotide precursor, a ribonucleoside phosphoramidite, and activator are added, coupling the second base onto the 5′-end of the first nucleoside. The support is washed and any unreacted 5′-hydroxyl groups are capped with acetic anhydride to yield 5′-acetyl moieties. The linkage is then oxidized to the more stable and ultimately desired P(V) linkage. At the end of the nucleotide addition cycle, the 5′-silyl group is cleaved with fluoride. The cycle is repeated for each subsequent nucleotide.

[0140] Following synthesis, the methyl protecting groups on the phosphates are cleaved in 30 minutes utilizing 1 M disodium-2-carbamoyl-2-cyanoethylene-1,1-dithiolate trihydrate (S₂Na₂) in DMF. The deprotection solution is washed from the solid support-bound oligonucleotide using water. The support is then treated with 40% methylamine in water for 10 minutes at 55° C. This releases the RNA oligonucleotides into solution, deprotects the exocyclic amines, and modifies the 2′- groups. The oligonucleotides can be analyzed by anion exchange HPLC at this stage.

[0141] The 2′-orthoester groups are the last protecting groups to be removed. The ethylene glycol monoacetate orthoester protecting group developed by Dharmacon Research, Inc. (Lafayette, Colo.), is one example of a useful orthoester protecting group which, has the following important properties. It is stable to the conditions of nucleoside phosphoramidite synthesis and oligonucleotide synthesis. However, after oligonucleotide synthesis the oligonucleotide is treated with methylamine which not only cleaves the oligonucleotide from the solid support but also removes the acetyl groups from the orthoesters. The resulting 2-ethyl-hydroxyl substituents on the orthoester are less electron withdrawing than the acetylated precursor. As a result, the modified orthoester becomes more labile to acid-catalyzed hydrolysis. Specifically, the rate of cleavage is approximately 10 times faster after the acetyl groups are removed. Therefore, this orthoester possesses sufficient stability in order to be compatible with oligonucleotide synthesis and yet, when subsequently modified, permits deprotection to be carried out under relatively mild aqueous conditions compatible with the final RNA oligonucleotide product.

[0142] Additionally, methods of RNA synthesis are well known in the art (Scaringe, S. A. Ph.D. Thesis, University of Colorado, 1996; Scaringe, S. A., et al., J. Am. Chem. Soc., 1998, 120, 11820-11821; Matteucci, M. D. and Caruthers, M. H. J. Am. Chem. Soc., 1981, 103, 3185-3191; Beaucage, S. L. and Caruthers, M. H. Tetrahedron Lett., 1981, 22, 1859-1862; Dahl, B. J., et al., Acta Chem. Scand,. 1990, 44, 639-641; Reddy, M. P., et al., Tetrahedrom Lett., 1994, 25, 4311-4314; Wincott, F. et al., Nucleic Acids Res., 1995, 23, 2677-2684; Griffin, B. E., et al., Tetrahedron, 1967, 23, 2301-2313; Griffin, B. E., et al., Tetrahedron, 1967, 23, 2315-2331).

[0143] RNA antisense compounds (RNA oligonucleotides) of the present invention can be synthesized by the methods herein or purchased from Dharmacon Research, Inc (Lafayette, Colo.). Once synthesized, complementary RNA antisense compounds can then be annealed by methods known in the art to form double stranded (duplexed) antisense compounds. For example, duplexes can be formed by combining 30 μl of each of the complementary strands of RNA oligonucleotides (50 uM RNA oligonucleotide solution) and 15 μl of 5X annealing buffer (100 mM potassium acetate, 30 mM HEPES-KOH pH 7.4, 2 mM magnesium acetate) followed by heating for 1 minute at 90° C., then 1 hour at 37° C. The resulting duplexed antisense compounds can be used in kits, assays, screens, or other methods to investigate the role of a target nucleic acid.

Example 4

[0144] Synthesis of Chimeric Oligonucleotides

[0145] Chimeric oligonucleotides, oligonucleosides or mixed oligonucleotides/oligonucleosides of the invention can be of several different types. These include a first type wherein the “gap” segment of linked nucleosides is positioned between 5′ and 3′ “wing” segments of linked nucleosides and a second “open end” type wherein the “gap” segment is located at either the 3′ or the 5′ terminus of the oligomeric compound. Oligonucleotides of the first type are also known in the art as “gapmers” or gapped oligonucleotides. Oligonucleotides of the second type are also known in the art as “hemimers” or “wingmers”.

[2′-O—Me]—[2′-deoxy]—[2′-O—Me] Chimeric Phosphorothioate Oligonucleotides

[0146] Chimeric oligonucleotides having 2′-O-alkyl phosphorothioate and 2′-deoxy phosphorothioate oligo-nucleotide segments are synthesized using an Applied Biosystems automated DNA synthesizer Model 394, as above. oligonucleotides are synthesized using the automated synthesizer and 2′-deoxy-5′-dimethoxytrityl-3′-O-phosphor-amidite for the DNA portion and 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite for 5′ and 3′ wings. The standard synthesis cycle is modified by incorporating coupling steps with increased reaction times for the 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite. The fully protected oligonucleotide is cleaved from the support and deprotected in concentrated ammonia (NH₄OH) for 12-16 hr at 55° C. The deprotected oligo is then recovered by an appropriate method (precipitation, column chromatography, volume reduced in vacuo and analyzed spetrophotometrically for yield and for purity by capillary electrophoresis and by mass spectrometry.

[2′-O-(2-Methoxyethyl)]—[2′-deoxy]—[2′-O-(Methoxyethyl)] Chimeric Phosphorothioate oligonucleotides

[0147] [2′-O-(2-methoxyethyl)]—[2′-deoxy]—[-2′-O-(methoxyethyl)] chimeric phosphorothioate oligonucleotides were prepared as per the procedure above for the 2′-O-methyl chimeric oligonucleotide, with the substitution of 2′-O-(methoxyethyl) amidites for the 2′-O-methyl amidites.

[2′-O-(2-Methoxyethyl)Phosphodiester]—[2′-deoxy Phosphorothioate]—[2′-O-(2-Methoxyethyl) Phosphodiesterl Chimeric Oligonucleotides

[0148] [2′-O-(2-methoxyethyl phosphodiester]—[2′-deoxy phosphorothioate]—[21-O-(methoxyethyl) phosphodiester] chimeric oligonucleotides are prepared as per the above procedure for the 2′-O-methyl chimeric oligonucleotide with the substitution of 2′-O-(methoxyethyl) amidites for the 2′-O-methyl amidites, oxidation with iodine to generate the phosphodiester internucleotide linkages within the wing portions of the chimeric structures and sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) to generate the phosphorothioate internucleotide linkages for the center gap.

[0149] Other chimeric oligonucleotides, chimeric oligonucleosides and mixed chimeric oligonucleotides/oligonucleosides are synthesized according to U.S. Pat. No. 5,623,065, herein incorporated by reference.

Example 5

[0150] Design and screening of duplexed antisense compounds targeting PTPN13

[0151] In accordance with the present invention, a series of nucleic acid duplexes comprising the antisense compounds of the present invention and their complements can be designed to target PTPN13. The nucleobase sequence of the antisense strand of the duplex comprises at least a portion of an oligonucleotide in Table 1. The ends of the strands may be modified by the addition of one or more natural or modified nucleobases to form an overhang. The sense strand of the dsRNA is then designed and synthesized as the complement of the antisense strand and may also contain modifications or additions to either terminus. For example, in one embodiment, both strands of the dsRNA duplex would be complementary over the central nucleobases, each having overhangs at one or both termini.

[0152] For example, a duplex comprising an antisense strand having the sequence CGAGAGGCGGACGGGACCG and having a two-nucleobase overhang of deoxythymidine(dT) would have the following structure:   cgagaggcggacgggaccgTT Antisense Strand   ||||||||||||||||||| TTgctctccgcctgccctggc Complement

[0153] RNA strands of the duplex can be synthesized by methods disclosed herein or purchased from Dharmacon Research Inc., (Lafayette, Colo.). Once synthesized, the complementary strands are annealed. The single strands are aliquoted and diluted to a concentration of 50 uM. Once diluted, 30 uL of each strand is combined with 15 uL of a 5X solution of annealing buffer. The final concentration of said buffer is 100 mM potassium acetate, 30 mM HEPES-KOH pH 7.4, and 2 mM magnesium acetate. The final volume is 75 uL . This solution is incubated for 1 minute at 90° C. and then centrifuged for 15 seconds. The tube is allowed to sit for 1 hour at 37° C. at which time the dsRNA duplexes are used in experimentation. The final concentration of the dsRNA duplex is 20 uM. This solution can be stored frozen (−20° C. ) and freeze-thawed up to 5 times.

[0154] Once prepared, the duplexed antisense compounds are evaluated for their ability to modulate PTPN13 expression.

[0155] When cells reached 80% confluency, they are treated with duplexed antisense compounds of the invention. For cells grown in 96-well plates, wells are washed once with 200 μL OPTI-MEM-1 reduced-serum medium (Gibco BRL) and then treated with 130 μL of OPTI-MEM-1 containing 12 μg/mL LIPOFECTIN (Gibco BRL) and the desired duplex antisense compound at a final concentration of 200 nM. After 5 hours of treatment, the medium is replaced with fresh medium. Cells are harvested 16 hours after treatment, at which time RNA is isolated and target reduction measured by RT-PCR.

Example 6

[0156] Oligonucleotide Isolation

[0157] After cleavage from the controlled pore glass solid support and deblocking in concentrated ammonium hydroxide at 55° C. for 12-16 hours, the oligonucleotides or oligonucleosides are recovered by precipitation out of 1 M NH₄OAc with >3 volumes of ethanol. Synthesized oligonucleotides were analyzed by electrospray mass spectroscopy (molecular weight determination) and by capillary gel electrophoresis and judged to be at least 70% full length material. The relative amounts of phosphorothioate and phosphodiester linkages obtained in the synthesis was determined by the ratio of correct molecular weight relative to the −16 amu product (+/−32 +/−48). For some studies oligonucleotides were purified by HPLC, as described by Chiang et al., J. Biol. Chem. 1991, 266, 18162-18171. Results obtained with HPLC-purified material were similar to those obtained with non-HPLC purified material.

Example 7

[0158] Oligonucleotide Synthesis—96 Well Plate Format

[0159] Oligonucleotides were synthesized via solid phase P(III) phosphoramidite chemistry on an automated synthesizer capable of assembling 96 sequences simultaneously in a 96-well format. Phosphodiester internucleotide linkages were afforded by oxidation with aqueous iodine. Phosphorothioate internucleotide linkages were generated by sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) in anhydrous acetonitrile. Standard base-protected beta-cyanoethyl-diiso-propyl phosphoramidites were purchased from commercial vendors (e.g. PE-Applied Biosystems, Foster City, Calif., or Pharmacia, Piscataway, N.J.). Non-standard nucleosides are synthesized as per standard or patented methods. They are utilized as base protected beta-cyanoethyldiisopropyl phosphoramidites.

[0160] Oligonucleotides were cleaved from support and deprotected with concentrated NH₄OH at elevated temperature (55-60° C. ) for 12-16 hours and the released product then dried in vacuo. The dried product was then re-suspended in sterile water to afford a master plate from which all analytical and test plate samples are then diluted utilizing robotic pipettors.

Example 8

[0161] oligonucleotide Analysis—96-Well Plate Format

[0162] The concentration of oligonucleotide in each well was assessed by dilution of samples and UV absorption spectroscopy. The full-length integrity of the individual products was evaluated by capillary electrophoresis (CE) in either the 96-well format (Beckman P/ACE™ MDQ) or, for individually prepared samples, on a commercial CE apparatus (e.g., Beckman P/ACE™ 5000, ABI 270). Base and backbone composition was confirmed by mass analysis of the compounds utilizing electrospray-mass spectroscopy. All assay test plates were diluted from the master plate using single and multi-channel robotic pipettors. Plates were judged to be acceptable if at least 85% of the compounds on the plate were at least 85% full length.

Example 9

[0163] Cell culture and oligonucleotide treatment

[0164] The effect of antisense compounds on target nucleic acid expression can be tested in any of a variety of cell types provided that the target nucleic acid is present at measurable levels. This can be routinely determined using, for example, PCR or Northern blot analysis. The following cell types are provided for illustrative purposes, but other cell types can be routinely used, provided that the target is expressed in the cell type chosen. This can be readily determined by methods routine in the art, for example Northern blot analysis, ribonuclease protection assays, or RT-PCR.

[0165] T-24 cells:

[0166] The human transitional cell bladder carcinoma cell line T-24 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). T-24 cells were routinely cultured in complete McCoy's 5A basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence. Cells were seeded into 96-well plates (Falcon-Primaria #353872) at a density of 7000 cells/well for use in RT-PCR analysis.

[0167] For Northern blotting or other analysis, cells may be seeded onto 100 mm or other standard tissue culture plates and treated similarly, using appropriate volumes of medium and oligonucleotide.

[0168] A549 cells:

[0169] The human lung carcinoma cell line A549 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). A549 cells were routinely cultured in DMEM basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence.

[0170] NHDF cells:

[0171] Human neonatal dermal fibroblast (NHDF) were obtained from the Clonetics Corporation (Walkersville, Md.). NHDFs were routinely maintained in Fibroblast Growth Medium (Clonetics Corporation, Walkersville, Md.) supplemented as recommended by the supplier. Cells were maintained for up to 10 passages as recommended by the supplier.

[0172] HEK cells:

[0173] Human embryonic keratinocytes (HEK) were obtained from the Clonetics Corporation (Walkersville, Md.). HEKs were routinely maintained in Keratinocyte Growth Medium (Clonetics Corporation, Walkersville, Md.) formulated as recommended by the supplier. Cells were routinely maintained for up to 10 passages as recommended by the supplier.

[0174] Treatment with antisense compounds:

[0175] When cells reached 65-75% confluency, they were treated with oligonucleotide. For cells grown in 96-well plates, wells were washed once with 100 μL OPTI-MEMT™-1 reduced-serum medium (Invitrogen Corporation, Carlsbad, Calif.) and then treated with 130 μL of OPTI-MEM™-1 containing 3.75 μg/mL LIPOFECTIN™ (Invitrogen Corporation, Carlsbad, Calif.) and the desired concentration of oligonucleotide. Cells are treated and data are obtained in triplicate. After 4-7 hours of treatment at 37° C., the medium was replaced with fresh medium. Cells were harvested 16-24 hours after oligonucleotide treatment.

[0176] The concentration of oligonucleotide used varies from cell line to cell line. To determine the optimal oligonucleotide concentration for a particular cell line, the cells are treated with a positive control oligonucleotide at a range of concentrations. For human cells the positive control oligonucleotide is selected from either ISIS 13920 (TCCGTCATCGCTCCTCAGGG, SEQ ID NO: 1) which is targeted to human H-ras, or ISIS 18078, (GTGCGCGCGAGCCCGAAATC, SEQ ID NO: 2) which is targeted to human Jun-N-terminal kinase-2 (JNK2). Both controls are 2′-O-methoxyethyl gapmers (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone. For mouse or rat cells the positive control oligonucleotide is ISIS 15770, ATGCATTCTGCCCCCAAGGA, SEQ ID NO: 3, a 2′-O-methoxyethyl gapmer (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone which is targeted to both mouse and rat c-raf. The concentration of positive control oligonucleotide that results in 80% inhibition of c-H-ras (for ISIS 13920), JNK2 (for ISIS 18078) or c-raf (for ISIS 15770) mRNA is then utilized as the screening concentration for new oligonucleotides in subsequent experiments for that cell line. If 80% inhibition is not achieved, the lowest concentration of positive control oligonucleotide that results in 60% inhibition of c-H-ras, JNK2 or c-raf mRNA is then utilized as the oligonucleotide screening concentration in subsequent experiments for that cell line. If 60% inhibition is not achieved, that particular cell line is deemed as unsuitable for oligonucleotide transfection experiments. The concentrations of antisense oligonucleotides used herein are from 50 nM to 300 nM.

Example 10

[0177] Analysis of oligonucleotide inhibition of PTPN13 expression

[0178] Antisense modulation of PTPN13 expression can be assayed in a variety of ways known in the art. For example, PTPN13 mRNA levels can be quantitated by, e.g., Northern blot analysis, competitive polymerase chain reaction (PCR), or real-time PCR (RT-PCR). Real-time quantitative PCR is presently preferred. RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. The preferred method of RNA analysis of the present invention is the use of total cellular RNA as described in other examples herein. Methods of RNA isolation are well known in the art. Northern blot analysis is also routine in the art. Real-time quantitative (PCR) can be conveniently accomplished using the commercially available ABI PRISM™ 7600, 7700, or 7900 Sequence Detection System, available from PE-Applied Biosystems, Foster City, Calif. and used according to manufacturer's instructions.

[0179] Protein levels of PTPN13 can be quantitated in a variety of ways well known in the art, such as immunoprecipitation, Western blot analysis (immunoblotting), enzyme-linked immunosorbent assay (ELISA) or fluorescence-activated cell sorting (FACS). Antibodies directed to PTPN13 can be identified and obtained from a variety of sources, such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, Mich.), or can be prepared via conventional monoclonal or polyclonal antibody generation methods well known in the art.

Example 11

[0180] Design of phenotypic assays and in vivo studies for the use of PTPN13 inhibitors

[0181] Phenotypic assays

[0182] Once PTPN13 inhibitors have been identified by the methods disclosed herein, the compounds are further investigated in one or more phenotypic assays, each having measurable endpoints predictive of efficacy in the treatment of a particular disease state or condition. Phenotypic assays, kits and reagents for their use are well known to those skilled in the art and are herein used to investigate the role and/or association of PTPN13 in health and disease. Representative phenotypic assays, which can be purchased from any one of several commercial vendors, include those for determining cell viability, cytotoxicity, proliferation or cell survival (Molecular Probes, Eugene, Oreg.; PerkinElmer, Boston, Mass.), protein-based assays including enzymatic assays (Panvera, LLC, Madison, Wis.; BD Biosciences, Franklin Lakes, N.J.; Oncogene Research Products, San Diego, Calif.), cell regulation, signal transduction, inflammation, oxidative processes and apoptosis (Assay Designs Inc., Ann Arbor, Mich.), triglyceride accumulation (Sigma-Aldrich, St. Louis, Mo.), angiogenesis assays, tube formation assays, cytokine and hormone assays and metabolic assays (Chemicon International Inc., Temecula, Calif.; Amersham Biosciences, Piscataway, N.J.).

[0183] In one non-limiting example, cells determined to be appropriate for a particular phenotypic assay (i.e., MCF-7 cells selected for breast cancer studies; adipocytes for obesity studies) are treated with PTPN13 inhibitors identified from the in vitro studies as well as control compounds at optimal concentrations which are determined by the methods described above. At the end of the treatment period, treated and untreated cells are analyzed by one or more methods specific for the assay to determine phenotypic outcomes and endpoints.

[0184] Phenotypic endpoints include changes in cell morphology over time or treatment dose as well as changes in levels of cellular components such as proteins, lipids, nucleic acids, hormones, saccharides or metals. Measurements of cellular status which include pH, stage of the cell cycle, intake or excretion of biological indicators by the cell, are also endpoints of interest.

[0185] Analysis of the geneotype of the cell (measurement of the expression of one or more of the genes of the cell) after treatment is also used as an indicator of the efficacy or potency of the PTPN13 inhibitors. Hallmark genes, or those genes suspected to be associated with a specific disease state, condition, or phenotype, are measured in both treated and untreated cells.

[0186] In vivo studies

[0187] The individual subjects of the in vivo studies described herein are warm-blooded vertebrate animals, which includes humans.

[0188] The clinical trial is subjected to rigorous controls to ensure that individuals are not unnecessarily put at risk and that they are fully informed about their role in the study. To account for the psychological effects of receiving treatments, volunteers are randomly given placebo or PTPN13 inhibitor. Furthermore, to prevent the doctors from being biased in treatments, they are not informed as to whether the medication they are administering is a PTPN13 inhibitor or a placebo. Using this randomization approach, each volunteer has the same chance of being given either the new treatment or the placebo.

[0189] Volunteers receive either the PTPN13 inhibitor or placebo for eight week period with biological parameters associated with the indicated disease state or condition being measured at the beginning (baseline measurements-before any treatment), end (after the final treatment), and at regular intervals during the study period. Such measurements include the levels of nucleic acid molecules encoding PTPN13 or PTPN13 protein levels in body fluids, tissues or organs compared to pre-treatment levels. Other measurements include, but are not limited to, indices of the disease state or condition being treated, body weight, blood pressure, serum titers of pharmacologic indicators of disease or toxicity as well as ADME (absorption, distribution, metabolism and excretion) measurements.

[0190] Information recorded for each patient includes age (years), gender, height (cm), family history of disease state or condition (yes/no), motivation rating (some/moderate/great) and number and type of previous treatment regimens for the indicated disease or condition.

[0191] Volunteers taking part in this study are healthy adults (age 18 to 65 years) and roughly an equal number of males and females participate in the study. Volunteers with certain characteristics are equally distributed for placebo and PTPN13 inhibitor treatment. In general, the volunteers treated with placebo have little or no response to treatment, whereas the volunteers treated with the PTPN13 inhibitor show positive trends in their disease state or condition index at the conclusion of the study.

Example 12

[0192] RNA Isolation

[0193] Poly(A)+ mRNA isolation

[0194] Poly(A)+ mRNA was isolated according to Miura et al., (Clin. Chem., 1996, 42, 1758-1764). Other methods for poly(A)+ mRNA isolation are routine in the art. Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 60 μL lysis buffer (10 mM Tris-HCl, pH 7.6, 1 mM EDTA, 0.5 M NaCl, 0.5% NP-40, 20 mM vanadyl-ribonucleoside complex) was added to each well, the plate was gently agitated and then incubated at room temperature for five minutes. 55 μL of lysate was transferred to Oligo d(T) coated 96-well plates (AGCT Inc., Irvine Calif.). Plates were incubated for 60 minutes at room temperature, washed 3 times with 200 μL of wash buffer (10 mM Tris-HCl pH 7.6, 1 mM EDTA, 0.3 M NaCl). After the final wash, the plate was blotted on paper towels to remove excess wash buffer and then air-dried for 5 minutes. 60 μL of elution buffer (5 mM Tris-HCl pH 7.6), preheated to 70° C. , was added to each well, the plate was incubated on a 90° C. hot plate for 5 minutes, and the eluate was then transferred to a fresh 96-well plate.

[0195] Cells grown on 100 mm or other standard plates may be treated similarly, using appropriate volumes of all solutions.

[0196] Total RNA Isolation

[0197] Total RNA was isolated using an RNEASY ₉₆TM kit and buffers purchased from Qiagen Inc. (Valencia, Calif.) following the manufacturer's recommended procedures. Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 150 μL Buffer RLT was added to each well and the plate vigorously agitated for 20 seconds. 150 μL of 70% ethanol was then added to each well and the contents mixed by pipetting three times up and down. The samples were then transferred to the RNEASY 96™ well plate attached to a QIAVAC™ manifold fitted with a waste collection tray and attached to a vacuum source. Vacuum was applied for 1 minute. 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and incubated for 15 minutes and the vacuum was again applied for 1 minute. An additional 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and the vacuum was applied for 2 minutes. 1 mL of Buffer RPE was then added to each well of the RNEASY 96™ plate and the vacuum applied for a period of 90 seconds. The Buffer RPE wash was then repeated and the vacuum was applied for an additional 3 minutes. The plate was then removed from the QIAVAC™ manifold and blotted dry on paper towels. The plate was then re-attached to the QIAVAC™ manifold fitted with a collection tube rack containing 1.2 mL collection tubes. RNA was then eluted by pipetting 140 μL of RNAse free water into each well, incubating 1 minute, and then applying the vacuum for 3 minutes.

[0198] The repetitive pipetting and elution steps may be automated using a QIAGEN Bio-Robot 9604 (Qiagen, Inc., Valencia Calif.). Essentially, after lysing of the cells on the culture plate, the plate is transferred to the robot deck where the pipetting, DNase treatment and elution steps are carried out.

Example 13

[0199] Real-time Quantitative PCR Analysis of PTPN13 mRNA Levels

[0200] Quantitation of PTPN13 mRNA levels was accomplished by real-time quantitative PCR using the ABI PRISM™ 7600, 7700, or 7900 Sequence Detection System (PE-Applied Biosystems, Foster City, Calif.) according to manufacturer's instructions. This is a closed-tube, non-gel-based, fluorescence detection system which allows high-throughput quantitation of polymerase chain reaction (PCR) products in real-time. As opposed to standard PCR in which amplification products are quantitated after the PCR is completed, products in real-time quantitative PCR are quantitated as they accumulate. This is accomplished by including in the PCR reaction an oligonucleotide probe that anneals specifically between the forward and reverse PCR primers, and contains two fluorescent dyes. A reporter dye (e.g., FAM or JOE, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, Iowa) is attached to the 5′ end of the probe and a quencher dye (e.g., TAMRA, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, IA) is attached to the 3′ end of the probe. When the probe and dyes are intact, reporter dye emission is quenched by the proximity of the 3′ quencher dye. During amplification, annealing of the probe to the target sequence creates a substrate that can be cleaved by the 5′-exonuclease activity of Taq polymerase. During the extension phase of the PCR amplification cycle, cleavage of the probe by Taq polymerase releases the reporter dye from the remainder of the probe (and hence from the quencher moiety) and a sequence-specific fluorescent signal is generated. With each cycle, additional reporter dye molecules are cleaved from their respective probes, and the fluorescence intensity is monitored at regular intervals by laser optics built into the ABI PRISM™ Sequence Detection System. In each assay, a series of parallel reactions containing serial dilutions of mRNA from untreated control samples generates a standard curve that is used to quantitate the percent inhibition after antisense oligonucleotide treatment of test samples.

[0201] Prior to quantitative PCR analysis, primer-probe sets specific to the target gene being measured are evaluated for their ability to be “multiplexed” with a GAPDH amplification reaction. In multiplexing, both the target gene and the internal standard gene GAPDH are amplified concurrently in a single sample. In this analysis, mRNA isolated from untreated cells is serially diluted. Each dilution is amplified in the presence of primer-probe sets specific for GAPDH only, target gene only (“single-plexing”), or both (multiplexing). Following PCR amplification, standard curves of GAPDH and target mRNA signal as a function of dilution are generated from both the single-plexed and multiplexed samples. If both the slope and correlation coefficient of the GAPDH and target signals generated from the multiplexed samples fall within 10% of their corresponding values generated from the single-plexed samples, the primer-probe set specific for that target is deemed multiplexable. Other methods of PCR are also known in the art.

[0202] PCR reagents were obtained from Invitrogen Corporation, (Carlsbad, Calif.). RT-PCR reactions were carried out by adding 20 μL PCR cocktail (2.5x PCR buffer minus MgCl₂, 6.6 mM MgCl₂, 375 μM each of DATP, dCTP, dCTP and dGTP, 375 nM each of forward primer and reverse primer, 125 nM of probe, 4 Units RNAse inhibitor, 1.25 Units PLATINUM® Taq, 5 Units MuLV reverse transcriptase, and 2.5x ROX dye) to 96-well plates containing 30 μL total RNA solution (20-200 ng). The RT reaction was carried out by incubation for 30 minutes at 48° C. Following a 10 minute incubation at 95° C. to activate the PLATINUM® Taq, 40 cycles of a two-step PCR protocol were carried out: 95° C. for 15 seconds (denaturation) followed by 60° C. for 1.5 minutes (annealing/extension).

[0203] Gene target quantities obtained by real time RT-PCR are normalized using either the expression level of GAPDH, a gene whose expression is constant, or by quantifying total RNA using RiboGreen™ (Molecular Probes, Inc. Eugene, Oreg.). GAPDH expression is quantified by real time RT-PCR, by being run simultaneously with the target, multiplexing, or separately. Total RNA is quantified using RiboGreen RNA quantification reagent (Molecular Probes, Inc. Eugene, Oreg.). Methods of RNA quantification by RiboGreen are taught in Jones, L. J., et al, (Analytical Biochemistry, 1998, 265, 368-374).

[0204] In this assay, 170 μL of RiboGreen™ working reagent (RiboGreen™ reagent diluted 1:350 in 10 mM Tris-HCl, 1 mM EDTA, pH 7.5) is pipetted into a 96-well plate containing 30 μL purified, cellular RNA. The plate is read in a CytoFluor 4000 (PE Applied Biosystems) with excitation at 485 nm and emission at 530 nm.

[0205] Probes and primers to human PTPN13 were designed to hybridize to a human PTPN13 sequence, using published sequence information (a genomic sequence was assembled from contigs of GenBank accession number NT_(—)006122.3, incorporated herein as SEQ ID NO: 4). For human PTPN13 the PCR primers were: forward primer: CAAAGTCTGTTGCGAGTTTAAATAGAA (SEQ ID NO: 5) reverse primer: TACTTGGGATGAAGAGTTTCCAGAA (SEQ ID NO: 6) and the PCR probe was: FAM-CATTGAAGACCCTGGGCAAGCATATGTT-TAMRA (SEQ ID NO: 7) where FAM is the fluorescent dye and TAMRA is the quencher dye. For human GAPDH the PCR primers were: forward primer: GAAGGTGAAGGTCGGAGTC(SEQ ID NO:8) reverse primer: GAAGATGGTGATGGGATTTC (SEQ ID NO:9) and the PCR probe was: 5′ JOE-CAAGCTTCCCGTTCTCAGCC-TAMRA 3′ (SEQ ID NO: 10) where JOE is the fluorescent reporter dye and TAMRA is the quencher dye.

Example 14

[0206] Northern blot analysis of PTPN13 mRNA levels

[0207] Eighteen hours after antisense treatment, cell monolayers were washed twice with cold PBS and lysed in 1 mL RNAZOL™ (TEL-TEST “B” Inc., Friendswood, Tex.). Total RNA was prepared following manufacturer's recommended protocols. Twenty micrograms of total RNA was fractionated by electrophoresis through 1.2% agarose gels containing 1.1% formaldehyde using a MOPS buffer system (AMRESCO, Inc. Solon, Ohio). RNA was transferred from the gel to HYBOND™-N+ nylon membranes (Amersham Pharmacia Biotech, Piscataway, N.J.) by overnight capillary transfer using a Northern/Southern Transfer buffer system (TEL-TEST “B” Inc., Friendswood, Tex.). RNA transfer was confirmed by UV visualization. Membranes were fixed by UV cross-linking using a STRATALINKER™ UV Crosslinker 2400 (Stratagene, Inc, La Jolla, Calif.) and then probed using QUICKHYB™ hybridization solution (Stratagene, La Jolla, Calif.) using manufacturer's recommendations for stringent conditions.

[0208] To detect human PTPN13, a human PTPN13 specific probe was prepared by PCR using the forward primer CAAAGTCTGTTGCGAGTTTAAATAGAA (SEQ ID NO: 5) and the reverse primer TACTTGGGATGAAGAGTTTCCAGAA (SEQ ID NO: 6). To normalize for variations in loading and transfer efficiency membranes were stripped and probed for human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) RNA (Clontech, Palo Alto, Calif.).

[0209] Hybridized membranes were visualized and quantitated using a PHOSPHORIMAGER™ and IMAGEQUANT™ Software V3.3 (Molecular Dynamics, Sunnyvale, Calif.). Data was normalized to GAPDH levels in untreated controls.

Example 15

[0210] Antisense inhibition of human PTPN13 expression by chimeric phosphorothioate oligonucleotides having 2′-MOE wings and a deoxy gap

[0211] In accordance with the present invention, a series of oligonucleotides were designed to target different regions of the human PTPN13 RNA, using published sequences (a genomic sequence assembled from contigs of GenBank accession number NT_(—)006122.3, incorporated herein as SEQ ID NO: 4; GenBank accession number D21209.1, incorporated herein as SEQ ID NO: 11 and GenBank accession number U12128.1, incorporated herein as SEQ ID NO: 12. The oligonucleotides are shown in Table 1. “Target site” indicates the first (5′-most) nucleotide number on the particular target sequence to which the oligonucleotide binds. All compounds in Table 1 are chimeric oligonucleotides (“gapmers”) 20 nucleotides in length, composed of a central “gap” region consisting of ten 2′-deoxynucleotides, which is flanked on both sides (5′ and 3′ directions) by five-nucleotide “wings”. The wings are composed of 2′-methoxyethyl (2′-MOE)_(n)ucleotides. The internucleoside (backbone) linkages are phosphorothioate (P═S) throughout the oligonucleotide. All cytidine residues are 5-methylcytidines. The compounds were analyzed for their effect on human PTPN13 mRNA levels by quantitative real-time PCR as described in other examples herein. Data are averages from two experiments in which T-24 cells were treated with the oligonucleotides of the present invention. The positive control for each datapoint is identified in the table by sequence ID number. If present, “N.D.” indicates “no data”. TABLE 1 Inhibition of human PTPN13 mRNA levels by chimeric phosphorothioate oligonucleotides having 2′-MOE wings and a deoxy gap TARGET CONTROL SEQ ID TARGET SEQ ID SEQ ID ISIS # REGION NO SITE SEQUENCE % INHIB NO NO 155753 Coding 4 87839 catggaaagcgaaggaccaa 86 16 2 155754 Coding 4 147233 atctagcaaaccccgcagga 82 17 2 155755 Coding 4 128314 ccgtggagaatgaatcatta 73 18 2 155756 Coding 4 105043 ggtggctgactccctccaga 89 19 2 155757 3′UTR 4 158467 cattttcatgaaaaagtata 0 20 2 155758 Coding 4 104377 ttcaggttcactaaggtgat 42 21 2 155759 Coding 4 131348 agcagagactggataacttc 21 22 2 155760 Coding 4 80766 agtctcatcatcacagtgca 83 23 2 155761 Coding 4 112541 agcttgcttatgggtggctc 82 24 2 155762 Coding 4 121334 attctgggtaattctagaac 75 25 2 155763 Coding 4 121303 ctaatctgactgttttggat 85 26 2 155764 5′UTR 4 35131 gatttcccagaaccagtttt 80 27 2 155765 Coding 4 115944 aggaaagagctttttaaccc 5 28 2 155766 Coding 4 108843 gcatgtaggaagatttcttc 86 29 2 155767 3′UTR 4 158029 tattttggatagagagcagg 77 30 2 155768 Coding 4 104830 tcaagcatccatccaagtca 51 31 2 155769 Coding 4 121355 agcaaatgaggcaacattgg 86 32 2 155770 Coding 4 18381 cagtgaatgctcgaagatcc 82 33 2 155771 Coding 4 147200 ttttaagttggcacccgtgt 76 34 2 155772 Coding 4 68181 aagggtgtttcatattgtct 75 35 2 155773 Coding 4 108884 ccagtggtgatccttggaag 76 36 2 155774 Coding 12 4553 agatgaaccacctgtcctgt 85 37 2 155775 Coding 4 96628 gtttgttgagggtgctgctg 90 38 2 155776 Coding 4 68226 tcttgccgttttagcatgat 81 39 2 155777 Coding 4 116032 gctgagatagtcctttcaaa 83 40 2 155778 Coding 4 120572 cggtccccaggttttagcct 74 41 2 155779 Coding 12 7307 acctctctggtctgaatatc 62 42 2 155780 Coding 4 91065 agccatgttttattccatct 89 43 2 155781 Coding 4 131928 ctgataacttcccattcatc 57 44 2 155782 3′UTR 4 158081 ctaagatagaggagaacatg 33 45 2 155783 Coding 4 154480 ctcatgcagcgcaccaaatc 2 46 2 155784 Coding 4 117557 tttctgaggatagtaaaaca 75 47 2 155785 Coding 4 62541 atggactttcactggaggta 83 48 2 155786 Coding 12 508 gagaataaatgtggatcttt 72 49 2 155787 Coding 12 6241 caaccgtggagaatgaatca 57 50 2 155788 Coding 4 87790 caaggacacctttagaacag 59 51 2 155789 Coding 4 47286 agaaatcccatagatttact 65 52 2 194338 Start 11 55 gacacgtgcatattaccggc 83 53 2 Codon 194339 Coding 4 7248 tatttcttcctcctgaagtg 49 54 2 194340 Coding 4 47665 ggtgggcaattctcgagtgt 54 55 2 194341 Coding 4 91064 gccatgttttattccatctg 89 56 2 194342 Coding 4 105096 gataacaagtgtcacatcct 53 57 2 194343 Coding 4 108982 ctctcagtcctggaatcttg 78 58 2 194344 Coding 4 109209 agtaagtggcttcatccatg 87 59 2 194345 Coding 4 109236 ttggtgtttgatgatcctga 90 60 2 194346 Coding 4 110686 taaaattcatcttgttggat 33 61 2 194347 Coding 4 117553 tgaggatagtaaaacatggt 66 62 2 194348 Coding 4 121274 agcagattaactgcatctgt 75 63 2 194349 Coding 4 121692 caataccaatgaaggaagtg 51 64 2 194350 Coding 12 6873 aagattctccagctccttag 57 65 2 194351 Coding 4 151054 gtaaacgaactcttctttcc 58 66 2 194352 Coding 4 151066 ttggcaggcaatgtaaacga 67 67 2 194353 Stop 4 157962 ttttcatgtcacttcagaag 56 68 2 Codon 194354 3′UTR 4 158035 gatctttattttggatagag 71 69 2 194355 3′UTR 4 158314 ctactttattaaaatattgg 5 70 2 194356 3′UTR 4 158363 ctgtcatttaaagcttaaat 60 71 2 194357 3′UTR 4 158507 caaacagatgatgcagtaac 29 72 2 194358 3′UTR 4 158537 gtttttatttacaaagtgag 50 73 2 194359 Intron 4 65988 gtcacttctaaaacacattc 33 74 2 194360 Exon: 4 78432 tattacttacaagaatagac 19 75 2 Intron Junction 194361 Exon: 4 81704 ggatgcttacctttaaaaat 38 76 2 Intron Junction 194362 Intron 4 89466 ttgtaaaactctctcactga 42 77 2 194363 Intron: 4 108787 gtagaaggcactaaaagtca 0 78 2 Exon Junction 194364 Intron: 4 126462 aagatcatttctgtgttgta 0 79 2 Exon Junction 194365 Intron 4 138283 caagctgcagtgtcacaggt 75 80 2 194366 Intron 4 140406 ccattattattgtgtaggag 18 81 2 194367 Intron 4 47087 tccaaatggaagatcagagg 18 82 2 194368 Intron 4 47111 aagtggtggcaatttcctaa 66 83 2 194369 Intron: 4 47199 gagcttcttcctggaatgat 61 84 2 Exon Junction 194370 Coding 4 47229 ggcttttgtatgtctagtac 71 85 2

[0212] As shown in Table 1, SEQ ID NOs: 16, 17, 18, 19, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 71, 73, 80, 83, 84 and 85 demonstrated at least 50% inhibition of human PTPN13 expression in this assay and are therefore preferred. More preferred are SEQ ID NOs: 19 and 38. The target regions to which these preferred sequences are complementary are herein referred to as “preferred target segments” and are therefore preferred for targeting by compounds of the present invention. These preferred target segments are shown in Table 2. The sequences represent the reverse complement of the preferred antisense compounds shown in Table 1. “Target site” indicates the first (5′-most) nucleotide number on the particular target nucleic acid to which the oligonucleotide binds. Also shown in Table 2 is the species in which each of the preferred target segments was found. TABLE 2 Sequence and position of preferred target segments identified in PTPN13. TARGET SEQ ID TARGET REV COMP SEQ ID SITEID NO SITE SEQUENCE OF SEQ ID ACTIVE IN NO 71261 4 87839 ttggtccttcgctttccatg 16 H. sapiens 88 71262 4 147233 tcctgcggggtttgctagat 17 H. sapiens 89 71263 4 128314 taatgattcattctccacgg 18 H. sapiens 90 71264 4 105043 tctggagggagtcagccacc 19 H. sapiens 91 71268 4 80766 tgcactgtgatgatgagact 23 H. sapiens 92 71269 4 112541 gagccacccataagcaagct. 24 H. sapiens 93 71270 4 121334 gttctagaattacccagaat 25 H. sapiens 94 71271 4 121303 atccaaaacagtcagattag 26 H. sapiens 95 71272 4 35131 aaaactggttctgggaaatc 27 H. sapiens 96 71274 4 108843 gaagaaatcttcctacatgc 29 H. sapiens 97 71275 4 158029 cctgctctctatccaaaata 30 H. sapiens 98 71276 4 104830 tgacttggatggatgcttga 31 H. sapiens 99 71277 4 121355 ccaatgttgcctcatttigct 32 H. sapiens 100 71278 4 18381 ggatcttcgagcattcactg 33 H. sapiens 101 71279 4 147200 acacgggtgccaacttaaaa 34 H. sapiens 102 71280 4 68181 agacaatatgaaacaccctt 35 H. sapiens 103 71281 4 108884 cttccaaggatcaccactgg 36 H. sapiens 104 71282 12 4553 acaggacaggtggttcatct 37 H. sapiens 105 71283 4 96628 cagcagcaccctcaacaaac 38 H. sapiens 106 71284 4 68226 atcatgctaaaacggcaaga 39 H. sapiens 107 71285 4 116032 tttgaaaggactatctcagc 40 H. sapiens 108 71286 4 120572 aggctaaaacctggggaccg 41 H. sapiens 109 71287 12 7307 qatattcagaccagagaggt 42 H. sapiens 110 71288 4 91065 agatggaataaaacatggct 43 H. sapiens 111 71289 4 131928 gatgaatgggaagttatcag 44 H. sapiens 112 71292 4 117557 tgttttactatcctcagaaa 47 H. sapiens 113 71293 4 62541 tacctccagtgaaagtccat 48 H. sapiens 114 71294 12 508 aaagatccacatttattctc 49 H. sapiens 115 71295 12 6241 tgattcattctccacggttg 50 H. sapiens 116 71296 4 87790 ctgttctaaaggtgtccttg 51 H. sapiens 117 71297 4 47286 agtaaatctatgggatttct 52 H. sapiens 118 112450 11 55 gccggtaatatgcacgtqtc 53 H. sapiens 119 112452 4 47665 acactcgagaattgcccacc 55 H. sapiens 120 112453 4 91064 cagatggaataaaacatggc 56 H. sapiens 121 112454 4 105096 aagatgtgacactitgttatc 57 H. sapiens 122 112455 4 108982 caagattccaggactgagag 58 H. sapiens 123 112456 4 109209 catggatgaagccacttact 59 H. sapiens 124 112457 4 109236 tcaggatcatcaaacaccaa 60 H. sapiens 125 112459 4 117553 accatgttttactatcctca 62 H. sapiens 126 112460 4 121274 acagatgcagttaatctgct 63 H. sapiens 127 112461 4 121692 cacttccttcattggtattg 64 H. sapiens 128 112462 12 6873 ctaagqagctggagaatctt 65 H. sapiens 129 112463 4 151054 ggaaagaagagttcgtttac 66 H. sapiens 130 112464 4 151066 tcgtttacattgcctgccaa 67 H. sapiens 131 112465 4 157962 cttctgaagtgacatgaaaa 68 H. sapiens 132 112466 4 158035 ctctatccaaaataaagatc 69 H. sapiens 133 112468 4 158363 atttaagctttaaatgacag 71 H. sapiens 134 112470 4 158537 ctcactttgtaaataaaaac 73 H. sapiens 135 112477 4 138283 acctgtgacactgcagcttg 80 H. sapiens 136 112480 4 47111 ttaggaaattgecaccactt 83 H. sapiens 137 112481 4 47199 atcattccaggaagaagetc 84 H. sapiens 138 112482 4 47229 gtactagacatacaaaagcc 85 H. sapiens 139

[0213] As these “preferred target segments” have been found by experimentation to be open to, and accessible for, hybridization with the antisense compounds of the present invention, one of skill in the art will recognize or be able to ascertain, using no more than routine experimentation, further embodiments of the invention that encompass other compounds that specifically hybridize to these preferred target segments and consequently inhibit the expression of PTPN13.

[0214] According to the present invention, antisense compounds include antisense oligomeric compounds, antisense oligonucleotides, ribozymes, external guide sequence (EGS) oligonucleotides, alternate splicers, primers, probes, and other short oligomeric compounds which hybridize to at least a portion of the target nucleic acid.

Example 16

[0215] Western blot analysis of PTPN13 protein levels

[0216] Western blot analysis (immunoblot analysis) is carried out using standard methods. Cells are harvested 16-20 h after oligonucleotide treatment, washed once with PBS, suspended in Laemmli buffer (100 ul/well), boiled for 5 minutes and loaded on a 16% SDS-PAGE gel. Gels are run for 1.5 hours at 150 V, and transferred to membrane for western blotting. Appropriate primary antibody directed to PTPN13 is used, with a radiolabeled or fluorescently labeled secondary antibody directed against the primary antibody species. Bands are visualized using a PHOSPHORIMAGER™ (Molecular Dynamics, Sunnyvale Calif.).

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 139 <210> SEQ ID NO 1 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 1 tccgtcatcg ctcctcaggg 20 <210> SEQ ID NO 2 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 2 gtgcgcgcga gcccgaaatc 20 <210> SEQ ID NO 3 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 3 atgcattctg cccccaagga 20 <210> SEQ ID NO 4 <211> LENGTH: 161484 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 17385- 17484, 23162-23261, 30999, 84634, 137865-137964, 146521-146620 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 4 ttaatttcta ttgggtaagc agcttggcat ggaatggcta ggtcatatgt taagtgtata 60 tttaactttt taagaaacta tattaacagt tttccaaagt gtgccatttt acattcccac 120 tagcaacgta tgaaaattcc agtttctcta catctttgtc aatacttagt atgctttgtc 180 aacacattgt ggttaatctt tttaatttta gatatcctca tagctatgta gtcatatctc 240 attgttttat ttttattttc ctaatgacta atgatgttga gaattgtttc atgtgctcat 300 ttgccagccg tatatcttct ctgatgtcca ttcaaatcta aaaaaaactg gattgtttgg 360 ttttttaatt atatattctg gatataagtc ctttatcagt tatatgattt gcagtatttt 420 tccttagttt gtggttcatt ttttttttta attttttttt ttattatact ctaagtttta 480 gggtacatgt gcacattgtg caggttagtt acatatgtat acatgtgcca tgctggtgcg 540 ctgcacccac taacgtgtca tctagcatta ggtatatctc ccaatgctat ccctcccccc 600 tcccccgacc ccaccacagt ccccagagtg tgatattccc cttcctgtgt ccatgtgatc 660 tcattgttca attcccacct atgagtgaga acatgcggtg tttggttttt tgttcttgcg 720 atagtttact gagaatgatg gtttccaatt tcatccatgt ccctacaaag gacatgaact 780 catcattttt tatggctgca tagtattcca tggtgtatat gtgccacatt ttcttaaacc 840 agtctatcat tgttggacat ttgggttggt tccaagtctt tgctattgtg aatagtgccg 900 caataaacat acgtgtgcat gtgtctttat agcagcatga tttatagtcc tttgggtata 960 tacccagtca ggacataggc gtgggcaagg acttcatgtc caaaacacca aaagcaatgg 1020 caacaaaagc caaaattgac aaatgggatc taattaaact caagagcttc tgcacagcaa 1080 aagaaactac catcagagcg aacaggcaac ctacaacatg ggagaaaatt ttcgcaacct 1140 actcatctga caaagggcta atatccagaa tctacaatga actcaaacaa atttacaaga 1200 aaaaaacaaa caaccccatc aaaaagtggg cgaaggacat gaacagacac ttctcaaaag 1260 aagacattta tgcagccaaa aaacacatga agaaatgctc atcatcactg gccatcagag 1320 aaatgcaaat caaaaccact atgagatatc atctcacacc agttagaatg gcaatcatta 1380 aaaagtcagg aaacaacagg tgctggagag gatgtggaga aataggaaca cttttacact 1440 gttggtggga ctgtggttca ttttttaaca gttctttctt ttcaaatagc aaagatgttt 1500 aattttgatg aattccagtt tatcaatttt gtttttctaa tctgggtcat gcatttgttt 1560 tcatatctac aaaaacattg gctaactgaa gtcaccataa ttttctccta actttttaat 1620 ggccttcaag accttattgt gtgcagaaaa gcttattgaa aattattttt aaatgaacat 1680 tcttattaca ttaaaaattc taaaacctat gtcttacttt ttttttaatg gggtcttgct 1740 ctgttgccca ggctggagtg gagtggtgca attatagcat tgcagtctcc acctcccagg 1800 ctcaagcaat cctcccatct caacctctca ggtagctggg actacaggca cgcaccatca 1860 tgttcagcta atttttttaa aaagcattat tatatataga gacgaggtat cgctgtattg 1920 cccaggcagt cttgaacccc tggactcaag tgatcctctc accttggcct cccaaagtgc 1980 tgggattaca ggcataagtc actgcacctg gccatagttc ttaagctttt aaggtcaatt 2040 taattatttt ttctatttat acatgcagaa aatttcaagg gaccctttga gtgtataatc 2100 tcattttcaa atttagtcag ttaacatccc ataaacactt taaactgcat tcatacaatt 2160 aaaagccaat ttttaaagta tttcttgtat ctgactgaca gaaaaaacct tcccaagtac 2220 ccaaataagt cttctaatga atgaaaactt atatagtaag acttatgtat agcaagcctt 2280 taagggtctc ttgtatgttc cagtggcatt ttgtatgttt taaaatacaa gcctcaacca 2340 ttttctcatt acactattta aattggaatc accatgcgaa tctgttattc taactcacct 2400 atttctccta gctaagatac tatatatgta cagattcttt aattttaaaa aatactaata 2460 tatgggctgt gtctcaaact tttctatact taattctgaa tcttcctgga tgaaaagatg 2520 cttacaattt tggggttgcc ttctcaactc actgtggttt tttaatgacc aaagatgtcc 2580 ttagcctgga tggtgagtga atccttgctc aaactagtgg catacacaga gctccatttt 2640 atagctgctt tgttcttgaa acagcatgtt tctattagcc ctatttcttt agattcaagt 2700 taaacattcc taattaatct gtctccagac aggttatttt atcacttgat tggatttagt 2760 taatctgttt actgttcatt ctgttctcaa tcactggtat gtactagctg tgcgtgccac 2820 aatccttcag gattaaaatg acatctgtta gaatctcctt gtggctttgt ctctgtgagc 2880 agttttaagg tcatgtcagt aatacctgtg ttaaccaaaa acataataat gattctggtt 2940 atgtgataga attaattttt cttatttgaa atttttttcc aaaaactttc tagttatcat 3000 gcagcatata accttcaaga gaataaaagt aaataatatg gctatgttta ttgtaaaatt 3060 taacctttgt gataggttaa tgtgataacg tctgttatat atctgtactc ccaagttacc 3120 tagtactgtg tctaaaggaa acaattgaag caataggctt taaaaaattt ttgtaactaa 3180 ttctgtcctc atctgttggt tgacttcaag cttttttccc tccattttct tttttctttt 3240 ttgcattcct cttcagcttc tgcatttctt tcattccctt gttatcttcg gagctaatga 3300 tctgaagtgc tataacagta aaataaacat gtgagagaga aagatggtgc tagtaggcaa 3360 tttataagct gatagctttg ttgtttgttt tctagaaagc tgctgtaata ctacattaaa 3420 ttctgacatt gggtaattag aatgaggcag ttttaaaaaa atctttaagt tcttgcctag 3480 caaagctgta aattaaaaat attaaatcta ttctgatagc ttgatgataa ctttgaaaaa 3540 caaatgttcc tttctatgtt ttggagttct aagaagttct aaccagaaat gttcataaag 3600 atcccatatt gaatatacaa aaaaagttta aataaaaatt aacacggtat tgatataatt 3660 cgtacccgat tcaatcaagc aacagaggta taattagcaa tctttgtagc tagaaaaatt 3720 aattgctgaa aaaattctat tgtgtgagaa gttactttta accttttcat ttttttattt 3780 atagggaata attatatttt aaaacccaat ttatttttaa aaagtaagga aaaacagtat 3840 cttaagattt aaaacctagt ctgtctcttg tgctctctat atatacacat aaatatatgt 3900 gtgtatgtat gtataaagcc aacatactgg ttttacaatg ggatacataa catatcatca 3960 taagcaacct aattttgttc tccttccttt tgtccttcca tccttcctta tatcaccaga 4020 ggaagttctg cctctatata aaaacccaga ttcataattc cctccttgcc ctttggtaat 4080 actaatgact acagtcactt aaactccata attaaaagta cctagtcagt atattaatca 4140 acctttcaat gtccattcag agctaaaact tttcccttcc ctagctaaga ttatctatag 4200 atggaagaca gtgtgattag cttctctttt tgttgcttat ctcctcaccc actggcaagt 4260 tgctatatct gaccccatca ggatctaaac caggggaagg aagagagaaa gcaaggcaaa 4320 cagtttttgt tgttgttttt cccacactcc tgttgtgaaa ttgctttact gtttttgaac 4380 ttgatatgtg tttaaggctg gccctttttc ttcggtgtgc ttttgtgggt tcttcacaat 4440 ccttcactgg aactacacta catgtgacac tccagaattt ttccctccaa ctagccagta 4500 acccctaacc cctctagccc tcagcctagt tttctttcag gccattccac agtagaaata 4560 attctaattt gaatccttct tctttctctt tctcctcttc tttcccttct ctccttttcc 4620 cctcctcccc ctgcgcctcc tcccttcttc ctttttcttg gtggtggtct gggtacttca 4680 ggtggaactc tgggtagaat tttttaaaca gcttttcgag atatacttca catacaataa 4740 aacttaccct ttaaaaaaat tctttttagt tttttagaaa cggtctcact ctgtcaacca 4800 ggctggagta cagaagcatg atcatagctc actgtaacct cagactcctg ggctcaagcg 4860 agcctccctt ttcagcctcc ttaataggta ggactacagt aggcaccacc atgcccggct 4920 gattttattt tttgtagaga tgagggtctc cccatgttgt ccaggctggt tttgaacttc 4980 tggcctgaag cgatcctcct accttagcct cccaaattgc tgggattaca ggcttaagcc 5040 actatgctca gccttcaccc ttataaagtg tacctttagt tatttttaga atttttgtgc 5100 aaccattgcc actatctaaa ttttaggaca ttttaatcct ctgggtagga tttcatatag 5160 gtccaagctg gccctctgtg tggccgtgct tccttgcccc tctcttaccc tgagcagtgg 5220 aagtatagct ggcttctgat acagtatgtc tcctcactct tgtgtgccct ccctctcctg 5280 tctacctcat gttgctgcct cagagtgata ggcaacacct ttagattcct aaagtgtgta 5340 ttaggcactg cctgatgtgc cctccactaa ctccagagaa catatatcaa ggactcccag 5400 gggtcccatt aaagcttctt tcactggctt gaggtgaaag gaaggcacct ttccacatcc 5460 ctcccacttt ggaggagaca tgaaaatcag cacacaactc tcttcaaaga aattcttgtt 5520 ctatctttgc tctactcttt ataccctgag tatatgcgtt agagctatct aaccagttct 5580 cagacatatt actttggaaa tttgctacag ggtagtcctt cacacaagtc atgttggtat 5640 ctgattgcta atattatctg atccctctgt tgaaacttcc aatttatcaa tatttttcat 5700 gtagaagata actcacatat ctttagaaag gaatgaagct tctacttttt tctcttgaat 5760 aaatatgcta ttatataata aagtcaatga gaacctagag actttggtgc aggcagggga 5820 tctaaataaa taatcgcact tcttgtacaa cctaagtaaa aacgcttttg gcttttttaa 5880 agcagtatct tatagtttcc ttttaacttt cacattgtgt atataagtag acaccctgga 5940 ggcagacttt aagcataaaa tgttttagta aacatttaaa aaggaaagtg aaaggacaag 6000 actggcctca tttatagttg gaattgcttt tttcagtcag gattaagtac cataaatgta 6060 aattaaaaga aaatagtagc ttgtcttgtt agttgagtaa acaaagtcaa cttttatcta 6120 aaacagatgt ttttataggt taacttttaa actccttatt tggcttcttt tccaaatctg 6180 cttctccctt acagtagaaa tatactatat atgttatgct taaattggtt ttgtctgggt 6240 agaaatctta tgaatcactc taaagaacaa ttttcaagct gtgtcaattt aggaaaattt 6300 atatagaagg attttaacta gttacatttt cctcttttaa catgaaaata ggcttattaa 6360 gccccataga aaatcttaag ttttatcagt atatcatcac ttaactgaac gccattggaa 6420 aaattgacct gacaaaaatt tcagcacaga cacttatctg atcttttatt aattcacctt 6480 ctgtagaatc atatatcaaa gcatgttcac aagcatagcc acttcccttg tcatagccac 6540 ccaaaatgac atttttattg ttactatcat tcctgtgtta caatagggaa acagaggttt 6600 aaaggaaaag tgactctccc agggaaaatg gtgagttgcc aacaaagctg ggtctggaaa 6660 tacttaattg catttagtgc aaaatataca gttatagtat atatattgga gataatagaa 6720 atcaactaaa gaatgaaaga aatgtgttcc atcttattcc caacttcccc taccatggct 6780 gtaggttctc ctctctattt ctctctactt ttatatctgg gatggatagg atgaaacctg 6840 gaacagaaat ctgaaaggcc ttcagttcag tctgactgct ttggtttatg atctgtattt 6900 tggtgcctcc tagtaccctg gggtctcttc ctttttccgt aaagcagtca ccacccccat 6960 tctccagttc tgtctctgaa gttgaccgtg ttgggctagg gcaagtggtt gttttgaggg 7020 tttttccctc caattccttt accttctgtg agtttaagat aacatttaga ttggtagcca 7080 tattgagaaa ttaggtagac agggggctta tagtctgtca tcactgatgt agagctttta 7140 ctactgcaag tatagttaag ttgctgatgc atagaccatc tgttaccttt gtttcccagg 7200 taatatgcac gtgtcactag ctgaggccct ggaggttcgg ggtggaccac ttcaggagga 7260 agaaatatgg gctgtattaa atcaaagtgc tgaaagtctc caagaattat tcagaaaagg 7320 taagctgctg ctgctgctgc tgttgttgtt gttgtttcag tattgggtac ttaaaaaaca 7380 gatacagggt cagagattag atttttgttt cattattcct gtgcctttgg cagagtatga 7440 aaggaatact ttccttatct cttttagggc tgaaaaagct cagctattat ctacattcat 7500 ttgaatatct tctatgtgcc caatattaca ccaggcagca aaagtgtaat ggtgattgaa 7560 accgaaacag ttcttctcag tttagagctc acagttcaat gtggaaaata gctattaaca 7620 aaatatttgg gccaggtgcg gtggcttaca cctctgttcc cagcactttg ggaggctgag 7680 gttggggtgt cacttgaggt caggcggttg agaccagcct ggtgaacatg atgaaacccc 7740 atctctacta aaaatacaaa atttagccgg tgtagtggtg ggcacctgta atcccagcta 7800 ctcgggaggc tgaggcagga gaatcacttg aatccaggag gtggaggttg cagtgagcca 7860 agattatgcc actgcactcc agcctgggtg acagagtgag actcctctca aaaaataaat 7920 aaatacacac acactcacac acgaacacat ttgtactgta taaacaaatg taaaaaatgc 7980 agccatgaca aaggctaaaa aggagggatt cagtgactct ctgagaactc ataataggag 8040 gatttgactt gatcatggca cagaaaagga aggctctcct acacaagcta agacccaaaa 8100 gaaaagttaa ccaggtgaga gggaggggaa aaaaatctgg tagaataata tatgcatccg 8160 tgttactcta aatcagaatg atatagggtc aacaagtatt ttggtgtttc cctgtggagg 8220 aggtcacttg gtccaaatgg ttttgcggca ttgtggagtt agaaaagtta gaatcatcct 8280 ttggttgtcc aaaaacattt gatatcatgc cagaagttgc acatgaagat gttgtttgcc 8340 attcatagca cctgaccaaa acttacttag aatagtaggt gaaaaaacca agcgtcatct 8400 aaagaatcag tctctaaaat tgatttgaat gcatacatca gacacaaaaa agcctgacag 8460 aaataagtaa ggattgaggg tagtgatagt tctgaaagtg tggtaccagc aacattagca 8520 tcttttgaaa acttgttaga aatgaaggca gaaataaaga tgttctttga aaccaacgag 8580 aacaaagaca caacatacca gaatctctgg gacacattca aagcagtgtg tagagggaaa 8640 tttatagcac taaatgccca caagagaaag caggaaagat ccaaaattga caccctaaca 8700 tcacaattga aagaactaga aaagcaagaa caaatacatt caaaagctac cagaaggcaa 8760 gaaataacta aaatcagagc agaactgaag gaaatagaga ctaaaaaaaa cccttcaaaa 8820 aattaatgaa tccaggagct ggttttttga aaggatcaac aaaattgata gaccgctagc 8880 aagactaata aagaaaaaaa gagagaagaa tcaaatagac gcaataaaaa atgataaagg 8940 ggatatcacc accgatccca cagaaataca aactaccatc agagaatact acaaatacct 9000 ctacgcaaat aaactagaaa atccagaaga aatggataaa ttcctcgaca catacactct 9060 cccaagacta aaccaggaaa aagttgaatc tctgaataga ccaataacag gatctgaaat 9120 tgtggcaata atcagtagct taccaaccaa aaagagtcca ggaccagatg gattcacagc 9180 cgaattctac cagaggtaca aggaggaact ggtaccattc cttctgaaac tattccaatc 9240 aacagaaaaa gagggaatcc tccctaactc attttatgag gccagcatca tcctgatacc 9300 aaagccggga agagacacaa ccaaaaaaga gaattttaga ccaatatcct tgatgaacat 9360 tgatgcaaaa atcctcaata aaatactggc aaaccgaatc cagcagcaca tcaaaaagct 9420 tatccaccat gatcaagtgg gcttcatccc tggggtgcaa ggctggttca atatacgcaa 9480 atcaataaat gtaatccagc atataaacag aaccaaagac aaaaaccaca tgattatctc 9540 aatagaggca gaaaaggcct ttgacaaaat tcaacaaccc ttcatgctaa aaactctcaa 9600 taaattaggt attgatggga catatctcaa aataataaga gctatctatg acaaacccac 9660 agccaatatc atactgaatg ggcaaaaact ggaagcattc cctttgaaaa ctggcacaag 9720 acagggatgc cctctctcac cactcctatt caacatagtg ttggaagttc tggccagggc 9780 aattaggcag gagaaggaaa taaagggtat tcaattagga aaagaggaag tcaaattgtc 9840 cctgtttgca gacgacatga ttgtatatct agaaaacccc atcgtctcag cccaaaatct 9900 ccttaagctg ataagcaact tcagcagtct caggatacaa aatcaatgta caaaaatcac 9960 aagcattctt atacaccaat aacagacaaa cagagagcca aatcatgagt gaactcccat 10020 tcacagttgc ttcaaagaga ataaaatact taggaatcca acttacaagg aacgtgaagg 10080 acctcttcaa ggagaactac aaaccactgc tcaaggaaat aaaagaggat acaaacaaat 10140 ggaagaatat tccatgctca tgggtaggaa gagtcaatat cgtgaaaatg gccatactgc 10200 ccaaggtaat ttatacattc aatgccatcc ccatcaagct accaatgact ttcttcccag 10260 aataggaaaa aactacttta aagttcatat ggaaccaaaa aagagcctgc atcgccaagt 10320 cagtcctaaa ccaaaagaac aaagctggag gcatcacgct acctgacttc aaactatact 10380 acaaggctac agtaaccaaa acagcatggt actggtacca caacagagat atagatgaat 10440 ggaactgaac agagccctca gaaataatgc cacatatcta caactatctg atctttgaca 10500 aacctgacaa aaacaagcaa tggggaaacg attcgctatt taataagtgg tgctgggaaa 10560 actggctagc catatgtaga aagctgaaac tggatccctt ccttacacct tatacaaaaa 10620 ttaattcaag atggattaaa gatttaaacg ttagacctaa aaccataaaa accctagaag 10680 aaaacccttg gtattaccat tcaggacata ggcatgggca aggacttcat gtctaaaaca 10740 ccaaaagcaa tggcaacaaa agccaaaatt gacaaatggg atctaattaa actaaagagc 10800 ttctgcacag caaaagaaac taccatcagg gtgaacaggc aacctacaga atgggagaaa 10860 atgttcgcaa cctactcatc tgacaaaggg ctaatatcca gaatctacaa tgaactcaaa 10920 caaatttaca agaaaaaaac aaccccatca aaaagtgggc aaaggatatg aacagacact 10980 tctcaaaaga agacatttac gcagccaaaa gacacatgaa aaaatgctca tcatcactgg 11040 ccatcagaga aatgcaaatc aaaaccacaa tgagatacca tctcacacca gttagaatgg 11100 caatcattaa aaagtcagga aacaacaggt gctggagagg atgtggagaa acaggaacac 11160 ttttacactg ttggtgggac tgtaaactag ttcaaccatt gtggaagtca atgtggcgat 11220 tcctcaggga tctagaacta gaaataccat ttgacccagc catcccatta ctgggtatat 11280 acccaaagga ctataaatca tgctgctata aagacacacg cacacatatg tttattgcgg 11340 cactattcac aatagcaaag acttggaacc aagccaaatg tccaacaatg atagactgga 11400 ttaagaaaat gtggcacata tacaccatgg aatactatgc agccataaaa aaatgatgag 11460 ttcatgtcct ttgtagggac atggatgaaa ttggaaatca tcattctcag caaactatcg 11520 caaggacaaa aaaccaaaca ccgccatgtt ctctctcata gatgggaatt gaacaatgag 11580 aacacatgga cacaggaagg gaaacatcac actctgggga ctgttgtggg gtggggggaa 11640 gggggaagga tagcattagg agatatacct aatgctaaat gacgagttaa tgggtgcagc 11700 acaccagcat ggcacttgta tacatatgta actaacctgc acaatgtgca catgtaccct 11760 aaaacttaaa gtataaaaaa aaaaatgcaa cagtaaaaca cacattagag acctactaaa 11820 taagcaactc tgggggtgca gcccagcaat ttgtgtttta acaagccctc aaggacattg 11880 tgatgcatgc taaagtttga gaaccattta taggatagag tttctaaaga ccaggagcca 11940 tgggaacctt ctggaaagat gtagggataa ctactgattg agtacaggaa ggtctagaga 12000 caggggaaga gtgtttgggg acagatggta aagctttgtt gtttttgttg ttgtttttta 12060 attcagagac aggattgtga aaaaacagtg ttagggccca cacatcagtg ctataacctt 12120 tatgtttgat gatctttaat tagagttagg attaatttaa agaaaattta ttcatttaat 12180 ctaatatcac ttaaccaaaa atctgggtgt tttaaataaa cattatttct ttgtttgctt 12240 cactttattt ttcagaaaat tttcagaaaa ttggaaagta tagacagtcc agaatataca 12300 ggatgtagct atactccaaa ggtgttattg aaggaaagat atgttgatgg cactattcag 12360 tcaattaata attgtcaatt aatatttaag aaataccttc tacttgtgag gtattgtgtg 12420 gaagatccaa ataagtaggt gtcacttttg cccttaaggg atttgttcag ataaaagaca 12480 caactgcaaa tttaccactt caaaacaaag tgccaaataa gtgacataga cgataagtac 12540 tacagatgtt cagaggaggg agagagaata cctcttttta ttatactaat ggcaggatta 12600 ctgcccaggc catgactcac agtatataaa gcatcttgca tactgtaagt acctaagggt 12660 ttttccttgt ttcacatttc ataatgttaa tagagatcaa atgaatataa aggtgttgtc 12720 actgagaggc aattattgca taacatattg gcacattata attaaaagac ttaccagatg 12780 tattataaaa ttaattgtga ggtagctgtg tcttaaatac tgtccagtag gagctggtta 12840 gcataaggcc tccagtctaa ttcacagagt attatcagta atacagagag attgaatttg 12900 gtttctttgg cagtttgaag attaccaatt gttatgattg ctaattggaa atttctattt 12960 atttggagga aacaaatgct tatttgattt aatttgtcag aaatttatga tttttcattc 13020 tttgtatttg ataacacaat atcttttttg tatatttgat cacacaatat ctttttgtcc 13080 caagttcttc tcctgactct tgtaacgaat tgaaataatt attagttttt ttattttatg 13140 gatgaatggt ggttgtctta gttctctctt agaatcctta tgcataacac tgggagtggc 13200 ggggggaaaa tagcaggtaa agtataatgg tgtccaagaa gtttatgtgt ttttttaaaa 13260 tgctttcttg tcaatggctt ttccccctta tcatcttgaa cttgtacgtt gttcctgttt 13320 ctttttcaga atatgagtgc aagcatgcta ctgacattcc tataagaggg ggctggaaat 13380 aagcatttct actggggtat tattgaacaa aagccaagaa aattatctgt ttcttcatat 13440 ttttgagcct cccagcaatc gaaggctttc catttttaaa agcaaaattg ctatggttat 13500 tattcatagg ataatgatat ctaagcatgg ccttgttgaa agacaccatc ttcaaatgaa 13560 cttctcttca gaggagggaa aatgtaaaac ttttgataat catgcaattc taacatgtag 13620 atgaaggtga tgaaaggtgg ttcccctttt ggtgtaagtt tcttagtttt gttgccttgt 13680 ggttactaaa acgtacaatc tgtatgacta ccctgagaaa tcatgagata gtattttttg 13740 agattttctt gtgatcttac acatgatcta tctttgtaaa tattctgtag gcatttgaaa 13800 agaattgtac tgtctattcc taggctatag cttaagctcg tgaatgtttg tgcttacaat 13860 ttttttaaac tttattagtc tgtattcttc atctgtcaaa ttcctaggga tagtcaaaac 13920 ttcccactat gattatattt ttgtctgtct tcttctgtag ttacatattt tcgcaatttt 13980 gtgtgataca tgtgatggct aatgactaat ataaatggac aagatatttt attaatataa 14040 agtaagtttt tttctttcta caagtcattg caataaattc tgttatctgc ccttaatatg 14100 gccacctttg cttcattttt gttgacactt gcctaccttt cctatctcta gtatagcttt 14160 cctccttcct ttattttcac atcctttatg ctataattta ggtacttttt gtgaatggta 14220 gatagctaga tttttatttt aacctagcta aggagttgct tttcttcaat taggaagtta 14280 attgtagtta ttgaaataaa agttctggga aattttacta agaatcttcc tgtgttatga 14340 tttcccagtt gtatgccttt cagttcatct tttcttttct tcttcttctt cttcttcttt 14400 tttttttttt ttttttttga gatggagtct cactctgtca ctcaggctgg agtgcagtgg 14460 tgcaatctcg gctcactgca acctccacct cccgggctca agcgattttc gtgtttcagc 14520 ctcctgagta gctgggatta caggcatgtg ccaccacacc cggctaattt ttttgtattt 14580 tttgtagaga cggggtttca ccatgttggc caggctggtc ttgaactcct gacctcaggt 14640 gatccaccca cctcggcctc tcaaagtgct ggaattacag gcgtgagcca ccgcgcctgg 14700 cccacttcac ctttttaact gattgagaat cctagcttat gtcagaaaaa catatataca 14760 tttaagattt tagcttttat atcatggatg aattcatgta ggagctcagt gttcctacat 14820 aataaaaaaa tgctattctc ctgctcttta tgaataatct ttagaagtga ggttattgct 14880 accttggaaa acttagctta caactgtagt aattgtccaa aacagtaatt ttttttgtta 14940 tggaactgtt gctctctgca gaaaacagct ctttcgaatc ttgaggtttt agggtgttag 15000 actgattgat tagtcagagg aagagactca atttccctca cttaggcaag gatataaatc 15060 cctttataag tagtcacttc tggttccctg tctaataaat aaaagaatta atgaaatgag 15120 taatttcaat aaaccgttaa aaagataata gaataaagca tttgataaag agaaatatta 15180 aaaacaagcc aggttcattg tctacattaa aaagttctaa gagataccag caagtgtcct 15240 gcaaaaattg aaagaccaca ttgtgtttct tatattcttt gaaagacaaa tttggatcag 15300 attgtagaga acagcttata taattatttc actgtatttc atttttatag tcttattata 15360 agtgaaaatg acaaattact atagaaagct aagacaaata tcaaatttca ctcctaaaaa 15420 agtgcctaaa aattagaatt tatagacaac tttaaaaaat cttattaggg aataaatctg 15480 ttaaataata tcagcaaagt ttagtgaata ttatgttctg ttttttatac aattactttt 15540 attgcataaa tactttcagg aaaattatct tgctactaaa agaaaaaagt gtgtatgaga 15600 aatacctaca tatactcaga accacacaca cttcttttat ttatggaatc aaactcttag 15660 agctgaaaag attttaatct gttcggtcta atcattttag agataaggaa acagcccagt 15720 ttaaatgact tataggagtt agtattggca gagcagaaat aatgtaacta ttttaaagca 15780 aatcattatg aacttacacc tatttagagc tataaaatca cttcatgtgt acataacaat 15840 gaagtttaaa aattgataac actcttatca atacagcaac aggaggttta caaaaacagt 15900 atcaggtgac atgatttcag attctatagt tatttaaaaa aataataagg gaaaatgatg 15960 aacaaagttg ttgaagtatt taacaactta catgaaatgg acatcttaaa agatacaaac 16020 agctcactca agaaaaaaat agacaacccg aattgtccta tatctattaa gatgattgat 16080 tttttttttt ttcttttcgg agacagaaat ctcactctgc cactcaggct gaagtgcagt 16140 ggcgtgatct tggctcactg taacctctgc ttcccaggtt caagctattc tgcctcagcc 16200 tcccaagtag ctgggactac aggtgtgtgc taccacgctc ggccaaattt tttttgtgtg 16260 tatttttagt agagatggaa tttcgccatg tttgccaggc tggtcttgaa ctcctgccct 16320 caagcgaccc gctcgcatca gcctcgcaaa gtgttaggat tacaggcatg agccaccaca 16380 cctggccaag gtgatttaat ttatagttta aaatacccca caaagaaaat tccaggccca 16440 tgttgtttca ctagggaatt ctactaaaaa tataaggaag aaataatagc acttctatac 16500 aaacactaat agaacattga agagaaggat gtacttccca actcattcat tctatgaggg 16560 cagcattact atgatttcaa aatcagacaa atacattaga gaaaaactac aaaccaatat 16620 gtcttatgaa catagatgca gaaattcttg agaaaacttt aattaattga atccaacaat 16680 atataaaaat gatagcacct catgatcaaa tggatcctag gaatgcaaga ttagttgaac 16740 tttcacaaat caatcaatat aattgaccat agtaatgact aaaaaagaaa actatattat 16800 ctttttaata gatgcagaaa aacatttggt aacatctaat atccatttca atcttaaaaa 16860 gctctcaact caacgccggg cttggcagct cacacctgta atcccagcac tttgggaggc 16920 tgaggcagaa gagactgctt gagttcagga gttcgtgacc agcctgcgaa acacggtgaa 16980 acctcatctc tacaaaaaat acaaaaatta gtcagacgtg gtgacatata cctgtagtcc 17040 cagctattca agaggatgac ttgagcccag gaggttgcag tgagccaaga tagcaccact 17100 gcactccacc ctgggcaaca gagttaggcc ccgtctccaa aaacaaacaa acaaacaaac 17160 aagcaaactc tcatctagga atagaaagga actacctcaa cctaataacg ggtatctaca 17220 catcatactt actggtaaaa cattgactct tcccctaaga tcaggaacag gtcaagggta 17280 tctgctctca ttacttatat tgaacattgt attctaagtt ctgactagta caaataaagc 17340 aagacaaata aaaggcatcc agattagaaa aaagcagaac tgttnnnnnn nnnnnnnnnn 17400 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 17460 nnnnnnnnnn nnnnnnnnnn nnnntgtatt tgtgttaata ctcttaggta tgagctctta 17520 ggcatctata cagccaagca ttaaaacaaa aagttaaggg acctcattga tcacatttgg 17580 tagtacaaaa caagctgcct gaaatgctag tgaaataatg aacaaatgta aataagataa 17640 aatctaaatt caagcaaaat atatacttcg actcaagaca tttcattgta gttagaaacc 17700 ttgtgaatgc ctaacaggaa ttttcaaagg aattgatttc tatccatttc agaacactat 17760 agtctaaatc ggaatcttaa cttgggatct ataaatgggt tataagtaga tccataaaac 17820 ttcagaattt atacagagct ttatatttat gggcaatgtc cttgagagag aaaccacacc 17880 tttcaccaat ttcttaaagg aatgcataat tcaaaaaaca ttaaagagct actaatcctt 17940 atccatatct atatgtcacg ttgataaaac atttgaacca agtttaattc ttaagaacaa 18000 tgaaagggct ctatttctag tttctaggat ctaccatcca gattttgaaa gattaagcca 18060 aatcaaggca ttgttgttaa taatgctacc tgttgtattt gtatgaaacc caatcttttt 18120 gtagcatgtt gatttggtat atgttaacta cttattaaca tctatacaaa taggctgcat 18180 tatccattga agtgattgct gtttcctgtg attataattt taagcaattt tcttcttttt 18240 ttttattttt tattttggtg caattacaaa ccagtaagcc tagctgatcc tgctgccctt 18300 ggcttcatca tttctccatg gtctctgctg ttgctgccat ctggtagtgt gtcatttaca 18360 gatgaaaata tttccaatca ggatcttcga gcattcactg caccagaggt tcttcaaaat 18420 cagtcactaa cttctctctc agatgttgaa aaggtaactg ttaaattttt ttgtttgttt 18480 ttttatttgg gtggggatag gtcaaataaa gacaatgggc taccatgttt caaccctctg 18540 aaaaatctat tgagttttaa atgaccgtgt attccaagaa gttcagttat tttatttaag 18600 aatccaaaat agttttataa agatttatgg atctgagaaa tatatgaaaa aaattaacca 18660 ttagaagcac atgtttacaa atacttatta aatacctgct ttgtataaaa caccgtgcct 18720 gaggaagata tagaaataac tggaaagttg accctgatta acatgtacag aacaatctgt 18780 aacagcaatc ctcatccttt ttggcaccag ggactggttt catggaagac agtttttcca 18840 aggatggggt ggtgggggaa tggttttagc aagaaactgt tccactcaga tcatcaggca 18900 ttagattctc ataagaagca tgcagcctca gtccctcaca tgtgcagttc ataataggat 18960 tcgcattcct atgagaatct aatgccaaca ttgatctgac aggaggcaga gctcaggtgg 19020 taacgttcac ttgcctactg ctcacttcct gctgtgcagc ctgcttccta ataggccatg 19080 ggactggtat ggggctggag gtgggggttg gggaccccga tctctaatat atggcaggat 19140 gaaataaatg ctatggagag tgatagtatt ttgagaatgt acaagatgag caattaattt 19200 ttagtgtaga atgatatcac agagaagagg tagctatttg tgttaggcta tgaagaatga 19260 atagacttca gataaataaa aataggtaga aagggcattc tactcagagt aattggtatg 19320 ggtaatgaca agaggtaaga aattgtccac tgtgattggg gaatggttgg ttagactggc 19380 taggctagaa tattactacc tagagggatg tggttaaagg aaggaagaaa ggctccaggt 19440 cagaaggagg atgatttttg aatgccagaa cttgaggctt tcttcttagg cagtggggat 19500 ctatcatatt tttaggagca tgactgatgt aatttgtgat tttggaggtt aaatttgaca 19560 aaagtagata actatgggag aaggaagatt ttgtgagtct ctaattgggg agttgttgtt 19620 gttttgtttt gttttgagac ggagtctcgt ttctttgccc aggctggagt gcagtagcat 19680 aatctcggct tactgcaacc tctgcctcct gggttcaagc aattctcctg cctcagactc 19740 ccaagtagct ggattacggg cacatgccag cacacctcgc taatttttgt atttttagta 19800 gagatggggt ttcaccatgc tggctaggct ggtcttgaac tcctgacctc aagtgatccg 19860 cctgcctcgg cctcccaaag tgctgggatt acaagtgtga gccgccgtgc ctggccaggg 19920 agttttaata ctctgtggaa aagaactgaa aatggcataa tgatttattt gatggcataa 19980 tgaagaagtg aaggtttaaa atagaagtat ccagtatgac tatagtgata taactgactt 20040 cagaataaga cctaatttta ttgtcaaagt tatgaaaaaa tttaggcata tatattgtgt 20100 tttatagcag acattaggta attgtgttat atagcaggct gtgggtaatt tagcactgtg 20160 gggtactcca gagaattcag aattggctat gaacattctt tcccatatgt cattccacat 20220 aagtgtaaaa attaacctag taatttccta atagcaaaat tgttaaatca aaaatacata 20280 catgttaaac ttcaatatac attgtctaat tgccatctaa aggaattcta atttctttaa 20340 actgacaatc atatttttct tttcagagat tgaatgtgta tgagtgtgtg tgtggtgact 20400 aagctaaagg aaggcatctt gatttgagcc atcaattatg tatctgaaaa aagactgaca 20460 agaattggta gagtgaattc agatttaaga ttatctacct ttgatattcc atgagctact 20520 taagaatttt gagaggtaca agcaaccatt gaaaggagat agtagttata aggtaggggt 20580 aatgcttaag gcattagact aaaaaatttc ccattacata agatgaagta tttgaaaaga 20640 attttttgta tgttacggag tagatatggt cttggtcatt gttatgtatc atgaaggtat 20700 tcaagtgtac cagtaatgtt ttattaagct ggatagtata catatatagt tattcatttt 20760 tattatttaa acaggatgca gtcattctgt acattgtacg attcatttaa taatattttt 20820 aaaaagggat tcgaacattg gaaataggta tagtatgtgt gcataggtat tatgaattct 20880 ttctgtaagc atttaaaacc cacaataaaa tttaaaaagt gcttagtaga aatttgggat 20940 gcacaagtgc ttttctgatt ttctgagagg tttcccaatt tgccttgtga tgtctagatc 21000 cccacacaag ttaaccctat gtttaggaat aactgttaga ccacatattt gggaaaatga 21060 ctaaagccac tctattattt tgccaagtgt ttagaagcaa tgttggggat gaaatgggtg 21120 tgggattgtt gccattatca tgttaaagtt gatttcttag tctgtctaat tggaacttct 21180 agcttacctc atgcctcaaa atcttaagtg taactctaaa tacaaagaaa atcaagtttc 21240 ttgatcctat tcataacatg aagcaaaggt cagaagagta gccatatatt ctagcacagt 21300 attctggttt taaaatggca agggcatttt gaaaatgagg aaagtagctg cacttaatta 21360 ctttcatgag ttaagaatat gctattaact agcactcaat aaatgcttgc tgttgatgac 21420 atataaattt tttataatgc tcagtgacca gcactcttga tacatgacaa tgttctcttc 21480 attcagaggg acttacactt aaaagtcttt cataaactgt acatgtttgt atgaaaaaac 21540 tcccttacta tcaactatgt aaacaggcat tttcatttat ttaccttaaa actttacttt 21600 tcaagataac atccctttaa atgagtagac aggtttatac aggctacact aagcttttta 21660 tcctctggct tttctctttt attgggtaat tttctacttc ctgcttgctt ggcagaaggt 21720 gtacttattt gacaattcct ttgaaatcgg tttgatggga tggaatttga atcaagttcc 21780 tgttgtgctt tctgttcaaa aatattgatg tgcaccagag atttgtacta tgtctctgat 21840 aaattaatct tgattattgc cactaatttg tagtctaaat atcaagaatt attgctctct 21900 gtgctttttg aaaatcaagg atcatcttta gaaagacaat aatagtaaat ctatttaccc 21960 aagcttagca gaagcctcaa ccgaacttga ccaaaaaaca acgaaatgcc cttaatcaca 22020 ctataccgta catactttgt attaaatctt gttaatccat tctctgtccc gttttcattc 22080 attcataaat ttgacaaatg tttgttatat gccaggaccc tgtgccactg aagaagaaat 22140 tctaggattg tctagtgaca cagtccaata tgtaatcata taattaaatt gaaaatgtta 22200 aatgttgggc ttgtagggat actatctcac atccattaca atggctacta tcaaaagaac 22260 aggatataac aactgttggc gaggatgcag agaaattgga acccttgtgt gttgttggtg 22320 agaatgtaaa attgtacagt cacaatggaa agcagtataa aggtttctta aaaaattaaa 22380 aatagaatta ccatatggtc cagcaactcc acttctgagt atatatatcc aaaataattc 22440 acagcaggaa ctcaaagaga tatttgcaca cccatgttca tagcagtgtt attcacaata 22500 gccaaaagct ggaagcagcc caaatgttca ttggcagatg aatggataaa aaaaactgtg 22560 gaatatacat acaatgaata tcatacaggc ttaagtaaaa ggcaggcttg tcacatgcta 22620 caatatggat gaacctggaa gacattatgt taagtgaaat aagccaatta caaaggacaa 22680 atactatgtg attccactca tatgaagtat ctaaagtagt caaaatcata gaaacaaaaa 22740 gtagaaaggt gattgccaag gactgggcag agagggtaga gggaagaatt agtgtttaat 22800 gagtatagag ttttagtttt gcaaggtgaa aaagttccag agattgttgc acaacagtgt 22860 aaatatgctt aacactactg aaatatatac ttaatggccg ggcacggtgg ctcacgcctg 22920 taatcccagc actttggaag gccgaagcgg gcagatcacg aggtcaggag atcgagacca 22980 tcctggctaa cacggtaaaa ccctgtctct actaaaaata caaaaaatta accaggcatg 23040 gtggcgggca ccagtagtcc cagctacttg cgaggctgag gcaggagaat ggcgtgaacc 23100 tgggaggcag agcttgcagt gagcggagat cgcgccactg cactcccaac ctgggcaaca 23160 gnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 23220 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn ntatatactt aaaaatagat 23280 ggtaaattta gtcttttttt ttttttttga gacggagtct agctctgtca ccaggctgga 23340 gtgcagtggc acgatctcag ctcactgcaa cctccacctc ccgggttcaa gtagttctcc 23400 tgcctcagcc tcccaagtag ctaggactac aggcgcatgc caccacaccc agctaagttt 23460 tgtattttta gtagagacag ggtctcacca tgttggccag gatggtctcg atcgcttgac 23520 ctcgtgatcc atctgcctcg gcctcccaca gtgctgggat tacaggcatg agccactgtg 23580 cccagccggt aaatttaatc ttgtgtgggt tttttttttt ttttaaccac aatgaaagat 23640 gatgccaagt cctagagttt taataggtgc aaaagcatta tagaaagtta ggtctttaaa 23700 tatcacttca ccatactatg ttccactagc taaaaaacta atttctggta atgttattgg 23760 agtgttaatg gcttaatgtt ttgctctagt cagataacac atttccatct tattagtttt 23820 taagtgtata tcatcttaac ttgaaggaat aactcttaag atggaaattt agccccatga 23880 gagagtactt agggcaccaa aatggatcct aaaataattc tatttcagca gatccctggg 23940 gccatttgca gttggtgggt ctcccctaga gcactagaac atgttttggt ttgcaataaa 24000 tgatactggt gttcctagtc ctacagtaag taacctagag ttaaataagt tgccagatat 24060 attgttaagc tattatatct tataaactaa ccatcacact cagtatgtaa agtgtgatga 24120 aatataaaag gtaatgtgtt gtggggaaag ggttaatttt aaaattagaa aataacaacc 24180 tgctgttttg agctttaaaa ataattttgg aggtgacttt taggaaatac cgaaagaaaa 24240 gagttatggc taaataaatt tgtgcaattg ctttatatat cagatcttaa cctaagttcc 24300 atcataccct cagaggtcaa aggaataagc ccaagaggcc attaaaagtt taaaaattgc 24360 atgcatacca aaaaaaatgt gtcttcgtat attcttctgg atagagggat catagctttt 24420 attcttcctt ctttctaaag ggctaaaaag tgattgacta tttgctgaca gatcccaaat 24480 gtatatatct ctagcaccat gctcttgact tttatgtaaa gctacttatt agatatcttc 24540 actggaatgt gccacaggca tctgagactc aatagatctg aaattaaact caatgtttct 24600 tcttataccc tgaaactttt ctcccttcca ttgtgtttcc tgtaaatgaa gggaccatca 24660 tttccccaat ttccaaggaa aaatctaagg tgtcattctt aatttttcat tcacctctgg 24720 ccccatttcc taaatcttac ggttaatttc ttttgagtct acctctttag tatatctcat 24780 atatgtctac atatattagc tttcactgct tccacctcag ttcagtccat cacaaatgac 24840 cagtgctgca aacacttcta ataatctccc aactccagtc ttgcccatgg ctagttcatt 24900 ctgtaaagta cagtctgcat ttttgaaaac ccatatataa tcttgttcta ttcctgttta 24960 aaattattca gattctccat gtcccctgaa tgaactcttg actcctgagg atggccttca 25020 agttcgtact gtattggcct tgtctgagcc gtctttattt caagctctgt gcttcaggca 25080 ttctgaattt actttagtgt ctgagatatg ccacatactt tctttcttct caacctttgt 25140 gcattctctt ctttcagctt tgaaaactct tttcacccag actcatgcta tttcaactga 25200 tctcctcact gtctggctaa cttttactgt agatgtgaag ctttctctta tgctctattg 25260 ttctctctgt gtacttctca catgtcacat tatcttatct tgtatacagc agtgaagatt 25320 tgatatggaa gggaccctgt ttgtcctcct cattattgta tcccctatgc tctctactag 25380 tggtcctcaa agtctggtcc ctccaatcag cagcatcacc atcacctggg aaacttttag 25440 aaaagcaagt tcttaggccc taccccagac ctattgaatc agataccctg gaggtgtgac 25500 gcagccacct atgttttatc aggcccttca ggtgattctg atgcataaca tagtttgaga 25560 acagttcctc tatgccatat ttggcaatga gtaaaaataa ttttttaacc cagaggtatc 25620 tatgatttgt tgccacacag tgccagggtt gtgttgctaa aaggagctat gtagcacatg 25680 taaagcagct catatttctt cacagagatc cagagatggc tgaatgagag gtatctgcac 25740 atcagactgc agtgtctcac ccagcctgtc tcttgtggtc agtgagacaa atctttgaag 25800 gcttttcgtc tcctctttag agaatggatc gagaggtaga aagtattctg ttagccttcc 25860 caatgatgat aattttatta tcccatttta tatttcaaca aatatttatc atatgtgggc 25920 tctggattga attctggctt tgtcacctaa gggatatatg aactcaggca atttgcttaa 25980 cctctccatg tcttaggtgc cttatctata tggtgttaat aatagtactt accttgtagg 26040 gtcattagaa agtgaaataa ggtaatactt gtaaagtgct tgggacagta cccagcatgt 26100 agtaagcatc caagaaatag taactatcac tattatatgt caaatgctgt gctaggtcta 26160 gggatagagt ggtaaacggg acaaaatccc tctgtgcatg gagtttatat tccagtatgt 26220 tataactgta tagacagaaa tgtatttctg tcctacagga cttatattaa tgagcttcct 26280 tgactctcat ctttccatgt cacattttcc tttctatcta tctctatcta tctatctatc 26340 tatctatcta tctatctatc tatctatctc tatctctatc tctgtctcca tctctggttc 26400 ctcccttttc acatatgtac ttaattgcct gaatttctca agtctgctaa gtttagccct 26460 tctaattctt tcctcttcag ccctattgct ggcactatgg tgaagttctc atttctcttc 26520 tctcggactt ttgtcatatc tcctaactct tattcctgct tcctgactgt tccctctgcc 26580 actgtcagat taatacccct gatcatgagg gtcttttccc ctcaaaaacc ttcattgagt 26640 tgctcctttt ttacccaatg aagtacagat tccttaacca aacatgaaaa tctctccaga 26700 gtctggtccc aactacctta tgactcctct tttttagatg cacaggctgt agccagtgat 26760 tattagacag atcttgtgct tctgggcttc acttctttgc atggcaatgc ctttctccct 26820 gttttcaggt ttccacatcc tgtgtaccat ccattctttc agggagcatc tactgaggac 26880 ttataatatg tccaacacta taaaaggtca aggagataca aagatgaata aggagtggac 26940 cttactctca aaggaccagg aggctgagag acaaagaaaa gatgatgatt ttgatgatgg 27000 tgatgatgat gatgatgtgc agggaatatg cacaatgata atagatctat acagaatatt 27060 aagagcagag agagggacac atagtctgtg ttccaagtct cagcttaata cccctctgct 27120 ttaagtttct tctaactcct ctgtagtcaa aataaccttt tcttgtctcc ttgagtttcc 27180 ttagcacaaa tttactactt tttttaatac ataggtgcat acatatatat ttatatctct 27240 ctcctgttag acttctaatt ctggaaaagg atatacagat taaattagta gttttcaacc 27300 agaggcagtt ttctctccta cggaacattt gacaatatct cggagacaat tttggttgtc 27360 ataactgaga gggtatgact agatagtact attggcatct aatgggtaga agccacggat 27420 cctgctctat atcctgcaat ttacagggca gctctcactg caaagaatca tccaatcgcg 27480 aatgtcagta gtgctgaggg catgacactg aagccaagtt agaatactgc cactgtcagt 27540 tctatagctg tgtgatcttg ggcaagttac cttccctctg taagattgaa tgagctaatg 27600 tatataatgt aggccgggcg tggtggctca cacctgtaat tccagcactt tgggagacca 27660 aggcaggcag atcacctgag gtcaggagtt caagaccagc ctggccaaca tggcgaaacc 27720 ccgtctctac taaaaataga aacattagct gggcatggtg gcaggtgcct gtaatcccag 27780 ctactcaaga ggctgaggca gggagaattg cttgaaccca ggaggcgaag gttgcagtga 27840 gctgagattg caccactgca ctccagcctg ggcgacagag tgagtctgtc tcaaaaaaaa 27900 gaaaaaaaaa ggaaagaaaa aaggaagaaa ttgttctaca atgtatataa tgtaagtttg 27960 gcacacagta agcattatgt acatgctagc tatttatatt ctaatacata taataatatc 28020 tattagctta tgatagtagt gttatagata ccaggatgaa atatttgtat cttatcacac 28080 tccctagttt agtgactttc agaaaaaatg ttgactaaat gggtagttgt ctagctcttc 28140 tatacatgca tgtcatctag aatcagctct tccatctttt cattgaatcc tgtatatatg 28200 aatcatcact atcaaaggca cctacctcta taggactgtg tcctggcctg ctatactact 28260 atactaagga agggaaatag agcatctctg tgctgtccgt aaggtacgga tggaccaaca 28320 aaggtcataa aaccacaaat tccctgggag gctaaataaa taagcaatac aagtgagaag 28380 cagatcaaaa cttttttttt tttttaactt gtactgcctg attctttttt cgccttggac 28440 ttgttgatat ctttaataaa agatttaata atcctggatt gtggattcct cttttttctc 28500 attacgtaaa acacaaagga aaatatgtag atcaaatact tgcctgtttt tgaataatcc 28560 ttcctgtgcg tgaccttcct cctttctaca caatatatat atgcagtctg taacccatct 28620 attgctgcta tttattaacc agatgaacta agcactgtca gtgatgtcag tgctgctata 28680 ttaatttagt tacatctttg tatcagtgat ctttatccct gtgtcttttc aggctgcacc 28740 agcagtacaa acgcttttaa tttatgaata aagtgtatgg aagcatcatg cacttaccct 28800 gtactgactg tttggggaat aaatgtaaaa gcatttttct ttgtattctg taagaaatat 28860 ttttctaata ttaggtacca ggttgtatta ccatgttatt ttaacaaaga tctgacatac 28920 ctggagttgt ctaacagctc aacaatgtat ttttaattat gatttaaaat attactaaaa 28980 gtgtggaacc catataaagt actgtcctaa taaagtagca attgtcattt tgcatatttt 29040 atttctctat agagatattt catacttata tgtattagtc aaggttctgc agagaaacag 29100 aaccaatagg gtgtgtgcgt gtgtgtgtgt gtgtgtgtgt atttgtatgt atagagaggt 29160 ttattataaa gggttggctc gtgcaattat gaaggctcac aagctccaag atcctcagga 29220 tgagtttgca aactggagat tcaggagagc caatgatgta gttcaagtct gagtccgaag 29280 gtcagagaaa cagtagaatt gctggtgtag ttctagttca aagactggca ggcttaagac 29340 ccaagaaggt ttcagtttga gtccaaagga ggaaaacact gatgttccag ttctaaggca 29400 gttaagtaga aagaattctc ttactcagag gagagttgac ctttctgttc ttttcaggcc 29460 ttcaactgac tggaaagggc ccacccatga tagggagggc agtctgcttt actcagtcta 29520 ctgatgtaaa tgttaatctc acccaaaaac actttcacag aaacacccag aatgagattt 29580 gaccaaatat ctgggcatcc tttggtccaa tcaagttgac acatacaact aactattata 29640 tgatatatat aggtgatcag caaatgtaca attttataac ctagttttaa gaatgtttta 29700 ttatagtcat gtataaaaat tattaacata tagtaactca cttggcatat tgagaagtaa 29760 gtataataaa gaatcttaaa gcatgggcca tatctcaaag aatcataaac caaaattaat 29820 ataattgagc atgcaattag tcctttatgc taaaactatg aaaaatgttt ttcatatatg 29880 aggttctttg aaaaggtatt tacacttaag actatttgga aagaagctta aagagaaata 29940 tgatacaaat agtctgcact aggctgtctt gaacttcttg cacatttaat ttaattcaac 30000 agacatgtat tgaatatctg ctatgtaaag ttctgtgtta cttgctaaga gggatactaa 30060 gatatgttaa aaaaaaaaaa aagctgtttc cctcaaggag gacaaacaag gactcatcta 30120 actatacaac aaggtaatag ttaactacgt catcaaagtg tggtgcagaa atataactgt 30180 atcatatatg agataatgct ttaacctgtt tggaagtatt tatacagcat atataagggg 30240 gaacatcatc actggcctat cagtaatggc cagagacaat atttttggtg gaaagaacag 30300 ctcacgaaaa gctgagaaag aaaaggatgt attttgccaa cagaaaatta tctagatgtg 30360 cctagtgttt aggttgtgat aagggaagga gcgatgacag aagaaaactt aaaaatctgc 30420 ttgcaaaatg gaaatagagg aaggtcacag tgagccctaa atgtcattat tttaaaattt 30480 gaatgtttaa aaattgagag ccatgaacat atttgaaaag tggaacaact tttctaatct 30540 gtaatttaaa aataatttag gaagcaatgt aagggatata ttaaagtgtt gtgagactgt 30600 aagaagggta cccactttta ttacatatat ctgactaatt tctaaagagg atttgataca 30660 gtttatagaa ttgaaaaata aaggtgaaaa aataggagcc gagtaaataa agacaagaaa 30720 ataagatgaa gctgtagtaa ggatgctgca aaacgaaaca acaacaacaa aagcacatgg 30780 caagaattca gtattgatag aagtggccca gaagatgagc tctgaatctc gacagaagga 30840 aataggaaag atgattactt ataactgaga tcttgctttt tgtgtcacag taaaaaaata 30900 gaagcaatca ggactttctc tatatatctc tagcagcctc cccgtgtgaa ttcccatatg 30960 ctctgccatc ttactacaga tgaactgtcc atgctcttnt ataaatccaa ctcctccatt 31020 tgtgctttag cttcaatctc cttatctact caacaatgtt cctctagcaa tctccattct 31080 ctcgtgcatt tccagttttc cctgttgaat catttctgtc agcataaaaa tatgttgagt 31140 ttttttaatc tttaagaaac aaacaaagca aacaacctaa agagaagtcc tttgattcag 31200 cttccttctc cttgtactac gctacccatt cattgtgaga aaatgcaaat caaaactgca 31260 gtgaggaaaa acaaaaaaca aaaaactgca gtgaggccaa gtgaggtggt tctcgcctat 31320 aatcccagca caccgggaag ccaaggcggg aggatctctt gaggtcagga gttcgagaac 31380 agccttgaca atatagtgag atcccatctc tacaaaaatt ttaaaagtta gccaggagtg 31440 gttttacatg cctttagtcc cagctatttg agaagctgag acaggaggat cacttgagtg 31500 atccaggagt ttgaagcaac agtgagctat gattgcacca cctcactgca gcctgggcaa 31560 cagagagaga tcctatcaaa aaacaaacaa aacaaaaacg gcagtgatgc agtgagattt 31620 attggtcaat ttttagattg gcaaaacgcc aagtctttgt aatacctcta tggaaaaggt 31680 ttgtgaaaaa ctcttacatg tacaaaaaca tgtggaaaaa ctcttacatg tacttctggt 31740 agaaatacaa aatggtacaa ctgttatgca agggaatctg acaatatata taaaaactgc 31800 agatgattta ctttctcatc cattatctca gaaaatccat ttaagagaaa tacttacaag 31860 gctgtttgct gaaacatcat ttgtagtagc aaaggtttga aaaaaatttt aattctctat 31920 taataacaga ttggttaaat aaacagtgct ttaaccacta atggaattct atataccatt 31980 taaaaaaata agatctctaa gcattgatat ggaaatacct attgataagt taaaaatgca 32040 aggtgcctgc caggcgcagt gggtcacgcc tataatccca gcactttggg aggctaaggc 32100 ggacagatta cctgaggtca ggaattcaag acgagcctgg ccaacatggc aaaaccccat 32160 ctctacttaa aatagaaaaa ttagtcaggc atggtggcag gcacctctaa ccccagctac 32220 tggggaggct gagccaggag aattgccggg ggatggaggt tgcagtgagc cgagattgtg 32280 ccactgcact ccagcctggg cgacagagcc agactctgcc tcaaaaaaaa aaagcaaggt 32340 gcctagtaat ttttaaggtt tctgaccttt tatgaaagga ggaaataaga atatatattc 32400 gtatttgctt gaatttgcat caggaacttt aaaagctaac aaaactgatt atgcataaag 32460 gatgggctgg ggaattagga aaacatctgt tgtaataatt tccagtcttg ctatctcttt 32520 taagctctca tatactttta tggaaaatat aaaatgatga ttttctcaaa ttgtgtatta 32580 tattttcttt ggaacaaaat aatctgtttt tatagcactt gcttaatttt ctattgtatt 32640 ttatcataaa attatttctt aaaaattcta ttcctagatc cacatttatt ctcttggaat 32700 gacactgtat tggggggctg attatgaagt gcctcagagc caagtaagtt aagtttttac 32760 agttgttata ctttttacat atgttcaatt ttacacctta tatcatagct cttccacacg 32820 tttatacgtg ttctacagca tgctgtcagg tgtaccaaca ttcctatgga gtttgtttac 32880 attaataatg tcatactttc aggatgaact ttcagtaaag tactaaagac actattttta 32940 aggtattcct agaattgtag caatcactac ccaggtttca acaactcagt ctgtgagatg 33000 gacctggcct cttcaaaaat tatagcaaga taaatgagcg tgtactttat tttatctaat 33060 gtagtgactg ttaagaggga ttgaaaatct cttgtctttg atgattcatt ctactgaatg 33120 taatagcttt tttgatgcaa aaactctagg aatagtagcc ctatgtctca gagtgttgta 33180 ttagagaatg tcatagcttt ttctcttggc acttcaaatc gtacatcata cttcacgacc 33240 cctgtaacag cagacacagg tattaaagta acacttgctg aggtcttggg ccctgtttgc 33300 cattgggctg cttctagtca ttattttcta aaataattct gattcttaat gaccaatata 33360 aacatagtag taaatagtaa ttgaaaattt aaaaatagct atatttcatc aaggcaagat 33420 ataacatata gaattaggtt ttattttagg catttataag tcaaaaccaa aaataactag 33480 gtgtggtttt ttcttattaa ataaaaggaa gtaacaagca ttttagcctt ttattctaaa 33540 atacaaacat cttaagatcc ataaaagata aataatattc ttcactttgt ttggttttat 33600 tttatatcat gaaaaataat gtatattttc tttttctctt cagtttcaat tctgtaaata 33660 taaatgagaa agttaaaata ttactggaaa tattggtgtc atatattatg caacctaact 33720 tgtaaaatgt gatcacagtc tataacactt tatgttcttt tctgataact ggaaataaag 33780 tcaatatcaa atataaatag agagtcaata tcaataaata taaattagag gggaaatata 33840 aacttgtatt ttaggatcag aaatcaggat attttggaaa tatttaatat taatttaaaa 33900 gtatttatta agtacctacc ttgtgtcaga tactgttaga cactaggact atagtgacgc 33960 ttgcctatgg agttttttgg aaggaacaga cagctaaacg gccaactgca acataatgca 34020 ataaatgcta tgttagggaa aatagaggat gctatggaaa acagagttgg gacttctggt 34080 taggcttgga gggtcaggac agatttctta aaggacattg catctaagct aacacctaaa 34140 ggatgatata ttaataatac ccaaatggat aagaagtgga agagtcatag gaaaggcatt 34200 tgtttagacc aaagtggata taccagttta aactcccgtc agcttggatg tgagttttaa 34260 ttgctccact ccttaccaat tcttgtattg ttagtatttt tatttttcac tattttattg 34320 ggtgtgtagt ggcttcttct tgtagtggtt ttaatttata tttcttagtg aataatgaca 34380 ttggccaccc tttcatatgc tctttggcca ttcagatata atattctaca aaatacgtta 34440 actaataaaa aaaaaaccct cacattctgg cttgtctgtt tgaccaacat aatgataatt 34500 tatatttaaa tggtcttgaa gcattgcaat attttaaatc ttctttaagt tatcatggga 34560 gtatctaatt atatttatac acattgaatg tattacattt tatataatat taggaaacag 34620 tttattcccc caaatggtgt gtatgtttgt gtgtgcgtgt gtacatgtag taactgttta 34680 tcaaaacatt tgaataagcc aagaatttca ctactttact ttatatttaa aaatgcccag 34740 agtttttctg tacttccttt ctagggaagt ataagttaac tatcttctgc taatatattt 34800 ttaaaaaagg taaaacacag taaaatgctt atgctgataa aaaggaattt atttcctcca 34860 agtatgtgaa gtgtgtttta gtgtggttcc tgtgattcct agaatgattt gtctcattag 34920 aaaaaatatt tgctcacatt tactcactgg cttttccttt atttatattc agcctattaa 34980 gcttggagat catctcaaca gcatactgct tggaatgtgt gaggatgtta tttacgctcg 35040 agtttctgtt cggactgtgc tggatgcttg cagtgcccac attaggaata gcaattgtgc 35100 accctcattt tcctacgtga aacacttggt aaaactggtt ctgggaaatc tttctggggt 35160 aagctacagt tacaatagta aatatagtca tattttaaaa tttagtagat atcacaaaat 35220 tttctttaag gatactatat aggtagcatt ttctcaatga agactagaaa tggaaaattg 35280 aatttcttct tctaatataa attgtttatt tgaaacaata cttaaaattt agaagctcat 35340 tgcaataagt ctagattttg tgagaattat tcccaaaaat atcatagaat gatagcatgt 35400 ttgagctgaa agtgtctcct cttgttttct ttcttagatc ttttcccaag gagcttttag 35460 caaatgcttc tattgtgaac acctagaaaa aatgtattaa catgaaaatg ggttttagaa 35520 atatttaaat gtactttctg ttgctttata cctgtttcgt gaccactcat ttgtctggat 35580 cttctaggta tttcccaaac cttctccact ttcccttctt ctcggaacac tgctacctag 35640 tgtatccagg gaatccatgc ttgtatccct gccagatttc cccaagacct ggactcttct 35700 agtttttctc ttgttttgga tatgaagaat cccaagaata accaatgcta tatattacct 35760 gaaagtccca cctctgttct gcatttctaa ggctgtattt tatcttgttt gccctatctg 35820 atctggatct atactttatc tgctcttatc cttagggttg tagtcctgga gtgttggtcc 35880 ctcttccttg cacaggttac aaatttacca ctgccacaca gtgttcttgt tgacttcctc 35940 agaattcctc atcggtaggg gtttagttcc catcttaacc aggatgtcag atggctgcca 36000 ggaatgtatt caaattctgc acagtttttc agttgataac aaacaggccc acagatcttc 36060 tagacaaatg gtttgtaaac tctccctcaa gaaacctttg cggttctata gtgaagggaa 36120 atgtaggaag tagaggccga ataaatggag ttcttggttg cccattttcc ctctttaact 36180 agagcagctc cagttttatt tgatctgttt atatttctgc gtgtgatttt tttgaacaaa 36240 ggtaaagcta ttaaaaaatc tttgaaaacc atctgtccag accaaagttt ctcatattgt 36300 tttcaatatt tttgttttaa aaattcctct atgaccaaat aagcttgaga agaaactatt 36360 taaaggaaat taaatgtatt ttcactggag aacttcttag aacctttaat atactagact 36420 atattactaa ccttcaagaa gaataggcat gtaaataaag catttcccaa actttcttgg 36480 tcttggaggt ctttttttca gacattctca taagactaat attctttaaa acttcacttt 36540 atggataagg aaactgatac ccaaacaact atgggatttg agtttcctat tagacagtcc 36600 agggactttt ttattacacc acactttctc taagactttt gtgctgcttg ctaattttac 36660 tcctatagta aaattgtgag agatattttt ttctgtcttt gaatgaagaa ttttttttct 36720 gtcaccatag aaattatatt acctatctaa taattgccca tattacatat aaaatcttca 36780 tccctttaag gtttagcatt tagttctctt tattatagtg gatctttatt gttcatttat 36840 gtatgaaacc tgtgctaggg attatagaag atacaaattt gaataaaata tttgatctag 36900 gagctcttat ctaaaatgcc ataaccattt gcttaattat aaaatgaaag aaggctataa 36960 aatgatacat agtaaaaatt ttaacagcta tgagagttta aaggaaaagg atacaaatta 37020 tgactgcatt gaaaaatagc actttgaagc tgagcatggt gatgcatgcc tttagtccca 37080 gctactcagg aggctgagat gggaggacta cttgagcctg ggaggtcgag gctgtagtga 37140 ggcatgattg caccactgca gtccaaccta ggcaacagag taaggcccta cctcaaaaaa 37200 aaaaaaaaaa gttaaaatta aaaatagcac ttcgaactgt atcctatagg ctagataatc 37260 tcggcagagg gaagtgaacc tggataaagg ctgtgaaatg ggaaagcagg aatgtttggg 37320 gaacagtatg acatggggtg tattgtgggg ttatttaatg ggagagaaaa atagaaggat 37380 cagttggaat cagcatgtag agagcctctc ttcacaaaga caaattttta ctaagtataa 37440 taatgctccc cttacctttc tattgctctt cctcatctcc tagacatcac tgggtagaag 37500 taactccaac agctactgtt ttttaagtgt ttgtttactt tgtgccagac actatgctaa 37560 ggggttgatg tgcattatca cattattcat cataacaacc tcaatttaat agagatactt 37620 ttatcctcat tttagagggc ataaaactaa ggctaagaaa gattaaataa cttgcacata 37680 gtcacagata cggtaaatga tggagacata attggaactg gggtgttttt gaccccagta 37740 tattccttaa agcttttgtt gcctccagta gctgacagaa tgagttagtc tttcactggt 37800 gtgaaattca ttctgagtga ccatcattct tacttaacat taattagcgt gagtaaaagt 37860 cagcaagcca gcttacttgt ctaggttttt ccactgattt aatgttataa tatttggacc 37920 acaattttac ttatctgcaa aataggaata ataataatat gtgtcaatca tccatattat 37980 taaactgttg taaaagtagt tatttccaca ttaatgagct gctttgtggt ccttagaagt 38040 ttctttgcta tttctccctt tatttataat atgaggataa tattgtctac catatgaggt 38100 tgtttgagga ttaaatagca caaagtgtgt gcctagcata tagtaactgt tcaataaaca 38160 acagttatta atagtaacta acttcaatgc aggaattttc aaagatgtgg gatgttagta 38220 atactgtctt ttcagtcact gacagtacag tgtaatctgg actaacatca tttatgcaac 38280 ttaactgata acatgatttc agaaatactt ccatttacaa gtcttcttat aggtagaaaa 38340 cataatgctt gagccttgaa tataccacct tagatgggtt tttaatccat acttcagcaa 38400 aattcactaa tggagcaata ttaaaacatt tctgtggtat gtgcgagttt gtgtgtgtgt 38460 aaacaaatat gtatgcatgc ttttggtgct agatttaagt aatttctctt caccattctc 38520 tcttcttcca tttatattga catttctcct ctatttggcc acctgaataa aacagtggtc 38580 tgtccagttt tttatccctt atagtgtgga gtttgaccta atttgacata ctttatttca 38640 agcagatacc ctttgctaaa gctattaaac tttaagatta cattttgttt taaagggaac 38700 ttaaaagagc attgatttaa atttgttatc cctcagagcg tccatttaaa gacttagcat 38760 ttctcggcca ggcatagtgg atcacgcctg taatcccagc actttgggag gccaaggcag 38820 gcagatcact tgatgtcagg agttcaagac cagcctggcc aacatggtga aaccctgtct 38880 ctacttaaaa tacaaaaatt agctggtgtg gtggtatgca ccagtagtcc cagctactct 38940 ggaggctaag gcatgagaat cgcttgaacc tgggaggcag aggttgcagt gaaccgaggt 39000 cctccaacct gggtgacaga gtgagactcc gttatattta aaaaaaaaaa aaaaaaaaaa 39060 agacttagca tttcacaaat gtaatttctg aagggcaaga tctataaaat tatttctgaa 39120 agtaatttaa attcctcaat tcatagttat aatcaagaga aagctttatt ataccaaaat 39180 taatgtggtt tttaaattat aaactaactt aagagtagtt agtggttggg gaaaaaagaa 39240 gacttcaagt ttactgtttt caaatagaac tcattttaac aagtttaatc tgatggtatt 39300 ttctagttag taggttactc ttcagtcact gcttcttccc ttttaatttt ctgaaatgaa 39360 ttggccagca ctggtctaca taaatcttat ccaagaatac aaattaccct acaaatacaa 39420 taggacatag agtctcatta tttaatgtta catcctccaa aaactgtgta actagtgtca 39480 ttctgtaaac agttaccatg aaaacaaaag ggagatcctt ttgtcaaact tgatttttta 39540 ttacctgtgt acagacagat cagctttcct gtaacagtga acaaaagcct gatcgaagcc 39600 aggctattcg agatcgattg cgaggaaaag gattaccaac aggtaagagt atattaatag 39660 gaaatgtcta ggctttaacc ttatcccatt gttttcttta caaaattata cttacctggc 39720 tttgaaatct ggtaattgag actatgatta gaacgtaaac gtacaaactg gaggtaggga 39780 atgggcagga acactagcta cattaaaaat aatttcatta aacttataca gaaaacatta 39840 ttaatatact taggattccc agagtaactt atttcccttt ccagtattgg tatatcaata 39900 ataataatat ttatttactt tatcgtggta tttcatatta aaaatacttt ttaaagcatg 39960 actaaataaa cacatgtata tgtttatgaa cataaacact actgaaacaa aagtttcaga 40020 aaacgttttt cttactgcac tctgatattt tttatcatat ttcttttttt ttttaaatgc 40080 tagtaataac tcactaaata gattttatca tggagttatc aaatactacc ttaggtcatg 40140 tgatacttag taaataaaaa ctaatgatga gtagtgattt tgctatttgt caatagcatt 40200 atataattct gtatcctatg ataagtatta aatttatttt tttgaaagaa atgaatggaa 40260 atttcaggcc aggcgtggtg gctcacgcct gtaatcccag tgctttggga ggctgaggtg 40320 ggcggatcac ctgaggtcag gagttcgaga ccagcctggc caacatagtg aaatcccatc 40380 tctctaaaaa tacaaaaatt agccgggcat ggtggcaggc acctgtaatc ccagctactc 40440 gggaggctga gacaggagaa tcttgaaccg gggaggcaga ggttgcagtt agccgagatc 40500 acaccactgt gctccagcct gggcaacaaa gagtgaactt ctgtctcaaa aaaaaaaaaa 40560 aaaaaaaaaa aagaatggaa atttcaaaca cttgaaataa aagtaaatat aattttatgt 40620 gacaatttat ttttcattgc tactttcagg catggcttat ttataaaata aacttttgat 40680 tttgttgatt atctttgttc tcttcttatc aagcagtttt gagaatcatg ataatctaaa 40740 cattaacaga aatacttttt tagatcttgt cctagatctt ggggctaggt agaagtaaat 40800 gtacagattg cttaaatata ttctaacaaa atatattcta attgatatag cttaataaaa 40860 tagattaaaa agttaagatt ttaatttaat cagagcatca gagaaacctg tcttacttaa 40920 aacctatgag caactctaat tgtgaaaaat aaatgtagac cttgactatc tggaccaaat 40980 gttttacaga gtcagaactc tcatatctga gaggaaggaa tgtgtcagtt aaagaaaagc 41040 agtaaaattg tttctaaggg agtgattttg taatggtaca gttaagtatc tgttttggtg 41100 cttccatttt aattattgtg aataaagact atctgaaaag atattttagc tttcatttca 41160 ttggtatagt aatttatttc tggttagatc agagtttttt tctaatgcat atatgattag 41220 tttatatatg ggccaaaaaa ataacagtgt ggtaacaatt ttgaaagtat ttttcatcct 41280 ttcttgcaaa tatttccttc ctatacttat gtccccatac tgtacttttg tcactttctt 41340 tttgtaggta aaaatatgtt tatttttata ctattctagg atttgagata gtatatagtg 41400 taaactttag cactaataat agcagcaatt tgttaattga tcaaatttgc agtcagtctc 41460 ctattttaga atcgaataat aacaaactta tagatgaata tcaatagcaa gctgaaataa 41520 tcttttggga gacatagtga acattttaat aagtagaaca ttagatttaa aagacatttt 41580 tgtttttctt acttatcttt ttctattttc tccctctctt tctttgctct ctccacctcc 41640 ctctttcctt tcctctctcc ctccctcctt tcttatttct ctttgttatt ctttctctaa 41700 cctctttcag cagttcccta ctatcatttc ctactaccat taagtggcca tgttatgtag 41760 ttgaagttta tttgcttatg tgttacttct tgatttagta actgtaatgt tgtattatta 41820 atttttgcag acagtgtatt tttctaagaa taaaaaatat tcacatatga tttatttatg 41880 tatatatgac ttccatccta tctccctttc cagtgtgggt ctgtagaaag aaaaaggtga 41940 gccttgcaat atttatcaaa ttgtaaggat tatcaaatgc taacataatt tagattttat 42000 tactttcaat ggttcagagg cttaatgttt cagaaattaa ttgttacata ttattttaaa 42060 gatagcaatt aagagattat actgagtcta tacctacttg ataacatatt tttaataggt 42120 tatttgtcat ttacatatat acgtatattt gtttcataaa ggacattcat aaaagttaag 42180 ctttctggac atatagatgc tggggatagg gaaaacctat attaagttca ttagttttta 42240 taggtgttca gtgtatattt gttgactgaa cgagaaaagg ttttatggaa atactggatt 42300 ttgaagtgta atatatttgt agtatacttc tttaatagct ccataaagaa atatgtgaga 42360 ctatggttta tttatttagc ctatgttaaa cattaagttg tatgcaaaag aaaaataaaa 42420 catcttgcct catattattg gaccattttc ttattataac aataaaaaca tcagaaattt 42480 taatccagat tttaatgcct tttatttgtg attttgtttt tataatacta agaaagattt 42540 agtattattg tctaatagtt ccttagaatt cttattatta atatgctgtt ctaatacaga 42600 taaggaagcg ttgactgtca tgactttaca aaattaacag agaaatcaaa tccttaagta 42660 gattgtttgt tgattttatc ctctaatagt catattggag aataaaatct cccttgtatc 42720 taaactcaag agaatttgtg agtaattaca attagtcact caggattaac caaattttgt 42780 ttgtgtttct atttttttta gtagagttaa aggtcctaat actgaaataa tagtcttatt 42840 tggatcaagt ataaggggag agtattcttt agaccttctt aaccatcagt gctttgcaca 42900 gtagtattgc acaagtgctc ttttcattta ccttttacaa attcataaaa cctcatttta 42960 aggacagaac caatataaat atactaatta tagccattac caggcagaag cattcagcag 43020 ctaatagtca actgcataga ctaattttaa aagtttaaga ttgaaaaaaa aattatctct 43080 tgaagaagta attcttctaa gacacctagg acacttggca gtgccagttc ttaactgtca 43140 gtggtcaatt gcagcaaagc aaccttgtga tacattatta ataaaacatt ttcttcagtg 43200 tgcaccaacc taaaatctgt atgtggtgat agcattagtt tattaggctc ctgactacag 43260 gagtagtctt taataaagaa aatgttaaga tggacaggga gatacagaat tagatggaaa 43320 gatgtatgca aatttgggga taatgcctta tacctagtga tttaattgtt cagctcaaat 43380 gtaataaaga tttttatcta taagtaaatg accttaaaag gtctcttctt atatcttacc 43440 tccaagatct gtcacagaag ctaaagccta aactagtggg ctctctgacc ctactttgtt 43500 acctaatact gccagtgctg attaaatagc ttcactgagc agaaagaaat caaacatttc 43560 ctgccaagct taaggtggaa acttacacta ttattcagat caacatggtg gtgctttaga 43620 acttacgcat attagtaata tcatgtttct ttcttttgaa acgcacttgg acacatttgt 43680 gaggatacat ggggacttgg ggagcctctt ttaatattga aatgccattt cgaagtttac 43740 ttctaagaga tgtgaatttt tgagtctggg tgaattgaaa ggtaaatgat gatatccagt 43800 gtaggataat gttaatcaca tataacaaaa atagttaaaa cacaatgtaa tttacaagga 43860 agttttttct aaaatttaac taaaataaat gggatgtgtt ctattacaaa gactttttat 43920 attcttgaaa tcttacccaa ggaatacaaa tatgaaatct tttatttgta aataaagtat 43980 atttattgtt tgccatttaa cttttagcaa gctatgcatt ctccagaagg aaaatgctta 44040 gggccattgc agtgatctag tcaagcaata atgttaattg gaaatagggt gatggcagtg 44100 gaattagaat acatgaaata ataagatgtc tttgagaatt taaatagcca tcatttactg 44160 ttggatttga tatggggatt aaataaggta aaagatttaa ggatggtgcc catatttctg 44220 ttttgaacaa tcagttgagt aattgggcca cttattgtaa taggaaagac tgggggagaa 44280 tggacagttc tggatgtacg aagcaaaaga tcagttttga gcatgttgca tttgagggtc 44340 ttctgaaata taagtagaag tttcattaca tatgattgga actcccagaa gaggtcggtg 44400 ctaagcatat caattgggag ttgtcaaggt atagatgata ttactgcctt gttaatggaa 44460 gaagttatat aaatacaaag tgagtagatg aaattctaaa actgacacct aaggaaatcc 44520 aacatttgga tatctcataa aggaagaaaa accaaagact aagaatgagc agtctgacag 44580 gtaggaggaa agcaggtatg taaagagagg aaagattgag taaaggatgg tcatcataac 44640 cagcttttac tgagaagtaa aatatgtata ccaaaatgtc catctgattt ggcaagcaga 44700 gatcattggt cataactaat gagagttgct aatgtataga gtagttggag gctgattaaa 44760 gtgggtacaa taatgaatgg gaagtaagaa atgggagata gcagtagcta gggggaaatg 44820 tggttaacag aggaagagtt tggtttggtt tgactatggg agatactagc ttatgttcac 44880 atactaatgg gaatattcaa cagaaaggaa gaatattgaa aatatgagga gatagcaaca 44940 gagaattaac gaaagaagta aagtctttga taaagtaaaa ttatgagggg ggaatccaga 45000 atacatattg gggattggcc ttcaactggc aggaaatttc atcgtttaag atggcaaaga 45060 aaagagtaga catagcctgg cacagtggct cacacctgta atcccagcac tttgggaggc 45120 tgaggtgggc agatcacgag gtcaggagat caagaccatc ctggctaaca tggtgaaacc 45180 ccttctctac taaaaataca aaaacaaaat tagcgtggtg gtgggcgcct gtggtcccaa 45240 ctactcggga ggctgaggcg ggagaatggc gtgaacctgg gaggcggagc ttgcagtgag 45300 ccaagatggc gccactgcac tcgagcctgg gagacggagc gagactctat cccccctcca 45360 aaaaaaaaaa gtagacatag gtagtataga attactcatg gaaagatgag aaagctctcc 45420 tccaacagct ccggttttcc tggagttatg acaacaccat cagccaaaag aatagggagt 45480 taagttagaa aatgtggaga atgaggaaaa gtgaaacagt cattgtggaa agtaagcaca 45540 ctgttaacat gtggtgttgc gtgtacaaag tgattgacta tgaatttatg gtgttgccaa 45600 atacccactt gtttgatgtt tttccaagtt ttaactgctt gtttggtagt caaggtagca 45660 ggataaggca gatggttaag ttcatctatg tgtggtttat gatccttgaa tcctttccat 45720 tcttttttta aatctattgt gttctatcaa ttttcaagaa tatctctgtt ctctattcaa 45780 taaaatttta aattaatgag ttccaaatgt ggtttgttta agaatataac atccctaaaa 45840 tactgtaaca cagacctatg tttatcagtt ttcaaattat cttaggttag aagctggagt 45900 ctgtgacaat ctgtgtctgg atgtggtatg gtatatttct tggtgttctt tatctgatgt 45960 gcccaaaata tagatgttat ccttatttac acttgagtag attcatggga agatgaggca 46020 caataaaagc acaatgtttt aatcttatcc ttaagcaatt atttgctgcc attctgaaat 46080 gaattccctt tttaaagatt ttttaaggta aaatttgtgt tcagggaatt aaagcttata 46140 gttgttacac taaagaggca attgatgtct ttaaataaat taacaagcaa tttattatta 46200 ttaaggtttt agtcattatt ttatattgta tagcagatag atatcacagc gatcacagaa 46260 ggtagcacat gaaatcttca gtgtttatgg gctattgagt tagtgactat aaaatattta 46320 cccgtatttc ttttttcagt agtggccata tatatgcttt tttgttgaat ctatggattc 46380 acaaaattaa tttctggatg gacatttttg gtgtgtgtca catttataga ctactgcctt 46440 ttaaaaaaaa gtaaaatgac tactgatttt taactatatc aaggactaaa gaataagagt 46500 tggtacttta ttacaattgg caaataatgg taaattatgt tctagaggaa aaaacttttt 46560 tagtgcatga gggtctgcca tggaaacagt aagtttcttt cataacttaa acacagtcaa 46620 aattatttgg atttcaaaca caaagttttc tgaaaacatg tctaattata ataaaatctt 46680 gatacttaag aattcgaaat gctacaatcc tatttccatc cagaatatag caagaattct 46740 ttgtttcttc cttaaatgta tgtatttaaa agatcgaaat atactagggc tttatagtga 46800 tatgacatac atttgagtta tacctttaga agttaaagta gttcactata cattccatta 46860 ctgccccaaa tcatttcttg gatagtgaat attcttccaa actggatagt tgtctgcttt 46920 tttaaaacca aataattcac atttgatgaa tataaaataa taccactcaa aaatgtcagt 46980 tcagtatatt gcttttatta gataagagac gatgaactat gaaaagttat gcaaacatag 47040 tatctctttc ctcttccact atgaccatca tcaccatccc atttcacctc tgatcttcca 47100 tttggagcat ttaggaaatt gccaccactt tcattgtcaa tagtggatta catttccatt 47160 tattttctaa aaattgtgtg catacatgat agattcttat cattccagga agaagctcta 47220 cttctgatgt actagacata caaaagcctc cactctctca tcagaccttt cttaacaaag 47280 ggcttagtaa atctatggga tttctgtcca tcaaagatac acaagatgag aattatttca 47340 aggacatttt atcagataat tctggacgtg aagattctga aaatacattc tccccttacc 47400 agttcaaaac tagtggccca gaaaaaaaac ccatccctgg cattgatgtg ctttctaaga 47460 agaagatctg ggcttcatcc atggacttgc tttgtacagc tgacagagac ttctcttcag 47520 gagagactgc cacatatcgt cgttgtcacc ctgaggcagt aacagtgcgg acttcaacta 47580 ctcctagaaa aaaggaggca agatactcag atggaagtat agccttggat atctttggcc 47640 ctcagaaaat ggatccaata tatcacactc gagaattgcc cacctcctca gcaatatcaa 47700 gtgctttgga ccgaatccga gagagacaaa agaaacttca ggttctgagg gaagccatga 47760 atgtagaagg ttagtaattc tgtgcatgtt tgagaaagaa ttgaagtatt ttaaatattt 47820 ttttgaaata aagaagggtt attaaattat tccacaagtc ttattttcac tgccaaattt 47880 ttgtaccctg gttagtctct tacttctctg tcaatttctg ttctcccttc catcaaaacc 47940 ctaattgaaa tactctgctt ccacaaagtc atccctaata aaaatgccca gtcacgttat 48000 agtctctcga tatttgggat agtatatttt tagattgtaa gcttctcaaa ggcaggaggc 48060 atattttcta cttctttttg cttaaattct ccaccatacc gtctaccatg cactatctca 48120 tgggaggctt cagtaaataa ctggtttgtg gaaataaaaa gcagttcatc aaaatcagca 48180 atgccggaga agcagaatag catggttatg gtgcattgct tctcaaacca ccagcttcaa 48240 attacaaatt ttgggggcac aactgtagaa gattataatt tactttgtct ggaataaagt 48300 tttgaatcca taccttttga atcatagtac attttaggtt tacagagtca gcctaggttt 48360 gaattagttc ctccattagt aactatgtgg tctttacttg ggcttcatct ctccaagtct 48420 aaattactcc atctataaaa tgggcttctc aaagtaggtt aattaggtaa tgaatgtaaa 48480 gtgattaata ttacattatt agtgtgagta atataaaaat aactttataa atggtaattt 48540 cttattctag agaaaaactg tttcaaaaat acttgatttc acacacaaaa ctcaatatgt 48600 tgattggagt aaaattatgt ccaagacata tggatagagg ctattttcag tataaataga 48660 tgtgacatat agaggctatt tttagtatga atagaagcaa gagaaaagaa gagataattt 48720 ttaatctaat tctgtacatt ttttaagatt caagttttat actgcccttg cttcctagac 48780 aaatcctagg acatagctga ttaaagacga ctttaagatc tttctagttc aaagaaaaga 48840 atgacataat taaggatcat atttattttt aagatcgtta ttctagtgta atatttttta 48900 ttaatatatt tcctttaaag tattctaaag atctgttgtc ctgttactta agtttcaggc 48960 atagctctgg agctgaacaa cataatttat gagttttgct gtactttgag taaaagaagc 49020 tttgcattgt tttttcaatt tcaggaattg aaaattagta aagaatttga aattatggag 49080 gaaattattg aatagttaat tgatatgggt tccgatataa catgaatttt tcaaaaacat 49140 tagccaactt tatgagatgg ttgtatataa ccttgatcga atactttcaa agataggaag 49200 taaaaattta gaaatttata ttatacacaa cttcacaact tttggaattg tgatagcaga 49260 gagattaggc actttctatg gtttaaaaga aaagtctcct tttttatgtt gtacaacagc 49320 tagtatatga acattaattt agtctgacct tctgtcaagc atgccctcat ggaaacaatt 49380 atataaagaa atcttgtcca ttgtgaaaaa aaaaaaacct tcaatgattc aaatagataa 49440 aaccattata gttttgaaat agaaataatg aagatatgta ccaatctata tgagtattta 49500 aaaggctgaa tggtatcttt tttttattgt gaatgttaaa aatgaaatta taggccaggc 49560 atggtgggtc acacctgtaa tcctagcact tttggaggtc aaggtgggag aattgcttga 49620 agtcagaagt tcaagaccag tctgggcaat atagcaagac ctcatatcta caaaaaaaat 49680 tttttaatta tccaagtgtg gtggtgcaca cctgtagttc cagctactca ggaggctgag 49740 gtgggaggat cacttgagct gagaagtttg aagctgcagt gatctgtcat caagccactg 49800 cactctagac tgtgcaacaa agcgagactc tgtctctaat gatagtaata ataaaattgg 49860 ccaggcgtgg tggctcatgc ctgtaatcct ggcactatgg caggctgaga cgagcagatc 49920 acctgaggtc gggagttcga gaccagcctc accaacatgg agaaaccccg tctttactga 49980 aaaaaaaata caaaaattag ccaggcatgg tggtgcatgc ctgtaatccc agctacttgg 50040 gaggctgagg ctgaggcagg agaatcaagt gaacccagga ggtggaggtt gcagtgaacc 50100 gagatcgcgc cattgcaccc cagcctaggc aacaaaagcg aaactccgtc tcaaataata 50160 atcattataa tttctaatgt ttttatgtgt gatctaagtt tcaaaacatt acttgtcttg 50220 atatttggta aattagtagt aatgtgaatt agcaaagctt gagatttttt ttttatactt 50280 gaaccttggt ttgagagtta aacaggaaaa acatcaaaca ttaatggaaa cgtatttaat 50340 ctgttaaatt ataccataat agtctattta atatatttcg tttgtttttc attaccaata 50400 acaaaatata ttagactatt gtagcatatg attctattat cttctcagtt aatgtgtatg 50460 cacatgtgta taagtgttaa ggaaactcag accatcttat ttctacatat gcttttatat 50520 ctgcaaagat gatacataat tcttgtagag ccttatttgt tcaaaaggta attacgtatt 50580 tgatacatca tttccagatt tagaaatttc gtatttgtta taggatgcac aaacaaaaga 50640 aaagcttttt aaaaaaaaat ctgctttcaa ttgttcgata taggacaatc ttgaaatctt 50700 tttaactagg gttttcaaaa gcatttgctc tcatgaagaa cctacccatt attcccccag 50760 aggatatttt acaacccagt taaacaaaca cctaaaaatg ttggattatt atggaaatac 50820 actaccttaa acctccatta ttatatagta acttgaaagc agcaataaat tatgtttgct 50880 ttagactaca ggcattaatc aaaaggaatg ttagaagttt agaattcaaa agcactaatt 50940 cttactagtt atttagttga gtaacttgct ggtcttatgc tgtgcttttt ctaaaggtga 51000 ggtaatttat gttgcaaaca aggctgggcg cggtggctga tgcctgtaat cccagcactt 51060 tgggaggcca gggcgggcag atcacgaggt caggagatca agaccatcct ggctaacacg 51120 gtgaaacccc atctctacta aaaatacaaa aattagcctg gtgtggtggt acatgcctgt 51180 agtcccagct attcaggagg ctgaggcagg agaatcactt gaacctatga ggcagaggtt 51240 gcagtgagcc aagatcgtgc cattgcactg cagcctgggt gacagagcaa gactccgtct 51300 caaaaaaaaa aaaaaagaca tgcgcaaaca aacgtgcagc ttgttaatat gaagatttta 51360 gctactatac aaagaaaaaa gaatagaaaa tcatgtaaat cccatttttc tcatttaatt 51420 ctagtgagag acaggcttca cagatccctt ttatgtgtga taaatcaagc agaactgtaa 51480 atatcaatgt atacatttta ttgtacacat ttctttctta aactatttgt gttttaaaag 51540 ttttaaaaag aaatgttttg tacaattttt gtgatcttta aatttggcag ctgctaatgg 51600 gtttcagtaa ttatagaatt agaagaggtc ttagagcaca tgttatcgaa acatattctt 51660 gggcttgtaa agatttaata acatacctaa gatcacataa tgagttaaag atagagtttt 51720 attattttgg agattgtaga ttttcatcat ggattttcag aatatcagtc taaggatttc 51780 ccactacatg tgacttaaaa aaaaaaaagg atgtattctc acattccttg agctgatata 51840 ataattggaa gaaacaaaat tgctaaattt taatttgttc tttgggtgtt ctaggagggt 51900 tattgagtta ataaacagtt ttctcctcca acctctgata atatagcttt ttccttaacc 51960 caggccccat tctcttgaaa ggatccttta cctaaataat ctcctcagca tttccccagc 52020 taacaacatc aactagctaa ctagcataag ggacacaaga ccttcaaatc atggaatttg 52080 gaagtggaag gaatctggat accatttaaa ccaaacatct cattttcaga ggtccagaga 52140 agtagactag tttgccaaag gagatacata attcataatt cataacagag ccatattttg 52200 aatcccagtc tctagagccc aattataaga ttcttccact ctgctgtcct gatttaaaga 52260 agagaccaga tacatgtcag atacatggtt gaaaagatgt tgttactgcc tgggacattg 52320 gacattcaac taactgcctt ccaagtccct taagtctctc cttaaaaaaa ttatataatt 52380 tttaatacag tgaaacaaga tagtattagg aaaggctaaa atgaggcact tttggttttt 52440 tctgtattaa accataaggt gcaggggtta aggtggaact ccattatgtt atctattgtg 52500 gtagatagta ttttggtggg gttctactat ggtcgaatct ttaaggcagc taatcctatg 52560 actgaccaga taggccataa attatcaaaa agcagtgatt ggcattgagt ggtctgattt 52620 ctttgggaac aaaatgagat aggaacaaaa aagatctcaa gaaagaaatt gtagttgaaa 52680 ttgaaaaatt ataaatagaa gattattact gcgattatta agttaacttt tcagatagtt 52740 ctctacatac gtaaagcagt agggaagggg caggaagaaa cataacttag gtttctcttg 52800 tagaaactag ttttaaaatt tgatgttgcc cttttttgct tcattctttt aattctactt 52860 ttttttcacc tcagcacagg actatctaat tctcctcttt tttctcagta ttttattttc 52920 tacctcttca actccatccc aagatctgag tagttgtctg ttttctaata ggagtatctg 52980 acaaatgtct ctttctgtct ttcttgtaat gtgattacca tacacgccct atccattgct 53040 ctgtgggttg gcagtagatt cctgattatg agagattgac ttggaaccag tactgtgagt 53100 acagagtgag cagtactccc acaccctggg tggggatcat taatagcatt tggcttccaa 53160 cagttgcaac tcctctgcat tctgcacaat actagaaagg aaagtatgaa gaacagatac 53220 aactaatttc tacaaaagtg gctatagtta agtgttattt gtttaatggg ctgttaatca 53280 acctagttca catcaaaatg aaatattgtt ttcttccttc tagtagtgtg atctctggtc 53340 ctagcctagt tttgctatcc tgtgactgcc ctgtgaacac agcttagact ctatgttgtg 53400 caactagaat atgtaaacac tcaagtatgg gaacccattc tcatttgagg aaccttaatg 53460 tttcatttga gaagattgaa tttaaaagtt tacattctta cagttacgct taagaaaagc 53520 aaagggatga atttataagt gtgtgagttc atgttcaagt attatgtgtg gtacttttag 53580 tatcttaata attttatgga gatatatata ttttttcaaa acatcttttt taaattctaa 53640 aactagtatt tctttacttc cctttgaata gcaagaaaaa aatgattgag ttattattta 53700 agttactccg tgagctaaaa taaataattt taatattaag tttctatttg atttatatca 53760 gttccacaaa agtaaatgag aataagcagg gattttctgt aatattggtc aaataccaca 53820 tgtatttcag gcattaatga cttaattact agattaagaa atcttaagta ttagattata 53880 aatgagatgc aaatatattt tgtttctctg aattataatg tagatagaat caacatctta 53940 gaaaggaaag aagtgtctac tgtgtttcca tggctggatt ttaaagagat ttgtaattta 54000 gaccagtatt gtccaacaga atttcttcaa tggaggaaat agtctatatc tgcacagtcc 54060 aactcagtag ctactagcta catgtgacta tggagcactt gcaatgtagg tagtgcaact 54120 gaggaactga atattttatt taaacttaca tagttacatg tggctagtag tcaccatatt 54180 ggacagtgca gctttagact attcccatat gatattaggt cagtataaaa taccaacact 54240 cagttgagga aagagtggct ttagaaccat ttgggagatg gtgagcaata aatcgttatt 54300 tagtttaagt aagaatacaa ctgagaatgt atatttactt ctcttctttc ggtttatcca 54360 agtggaaaaa taaaattaca tttttaaata ctagggaaaa ttaaaggtca aaccaataca 54420 gactttccag tgtctgtact catgataacg tgagatcaga gttcacagaa ataatatgtt 54480 cctttattgg aaatgagaga cctaatttaa atctactcat agcatggttc acatagaccc 54540 agtttggctt tgacatagcc actctctaag gacggattga tatgtcttaa gaaagatcga 54600 aaatggatct tactaacaat aggtatcatc acatttttta agacccagca attttaaact 54660 taagtgtttc cttatttcat cccagtcccc ttgtctctcc atttgtctct ctgccgtgca 54720 agtttgaata cctttattct ctgctatcag ccatttacca atgttccatc acctgaacag 54780 gataaaattc tagctccttg gatcatcata cttaaggttc cccatgatta tatctctcct 54840 ctcatctttt agcatttccc atatcacacc tcatactatc attctctccc tttctccctg 54900 tctccctccc tccctttttc tttctctcct ccccactccc ttctttctta ctctcttaca 54960 cacttttcct ccctccttgc ctccccagct ctgaatttgt gtgtatgtag agaaaaagaa 55020 atacatacac acacacatac acacacacac acacaaacac acacttgtgt ggatggatgc 55080 gtggatagat agatgattga ttgatagatc tacctgccta cttacctatc tacctattta 55140 taggccattt tatatttcct tgcctttatt cacacagcaa tctgccttaa gattcaaagc 55200 tttcggacac tgatgtttca ggaatctttc tctcacctcc ccagtttagg atgatgatgg 55260 gctgtttttc attgaaatta ttgcttttca ggagcttgtc tttcctcgta cagacctcaa 55320 aaatttggcc ttatctaatt catagctgta tccttagcat ctgccactat acctgacata 55380 taataggtac tcagtaagtg tttgttaata taaatggagt attacaatgt ggctattaaa 55440 gaattttaat atatgcagtg gtgctatttc agataatggg ttacaacaat attctctggc 55500 aagttatagt gaggacaaat cacacctcct cttcctccgt tttgtccaac tcataagagt 55560 aaactcacat acttttcaca tataacctga acaaccaaca gagaatgtaa ttcatttcct 55620 attgaactct gtactctttg aaagttttga aaaagacagt gaagtcgtaa caacagtgaa 55680 tccttgaaga ttctgaaaga gtgatacagt gagcctagcc gatgtcacag cccagctatg 55740 tggctactat atcacacaag acccccatag aaggaggtgg aaactgttca ttctttttga 55800 tatccctact ctgcatatat tttagatcta tagagtgact aacagtttgt ttacagagca 55860 cttcttcata tatccttctt tacttacata cattcactct tgtatgagct ttgttcaccc 55920 aggttaaaaa ttttattcat tatgtctagc tctcaaggga ttttagaaca tattctattg 55980 attgcaatgt ggtgtaatat ggaatacagt agactaataa acacaaaagg tacagtcgct 56040 aatctcccaa aattattctc ccataaagga agcatagaaa agaacactta atatatgaat 56100 acataatatt attactgtgt ttctctgctt tgtttgaaaa ttgaaatatt ttgttaggac 56160 ccatatcttt aaaaatgtga gattttaaaa atgttttata cttctgcact acaaaagcag 56220 tcattttatt tctcttcgaa acttgtgtct gtaatttggg tcatgtatta aaggtaaaga 56280 aatgtcaagg taaaagtggt tatttaattc ttgttgcaat tggctgagtc tcactttctg 56340 catattactt gtctgagctt gaatatgtgt cacttgtaaa tggtgtttct agattacaat 56400 ttgtgttggc ttagattcat cttaatgtga aaattgtaga ctttaatgtt tcatttgaaa 56460 tagctttata taaggccaga atattatgca aatcttcata atccaagtct gatctcctaa 56520 acatttaaag tatagtgtac atggtcacat gccacaactt tatatggtaa aagtgctaat 56580 tgtgttaagt ggtggtagaa attgagactt tcagttgtca agaacttatg gcaaaacaca 56640 cttgcctatt gaaaaatggc ttttcattgt tgctgtataa atggcatcaa tataatagag 56700 tcactgtgaa ttttgttcag aggataagat tacagataaa agctaataaa atatttgtta 56760 agtttttata cctcattctg acaaaaaata gtatactctt aattatggta aaatagtact 56820 agagatgaaa ggacatcttc taatgattat agaatctgta taactagact tctgtccaaa 56880 tcttaattct ttgttttttg gttttttttt gagagagggt ctcgctctgt ctcctaggct 56940 aggtgcagtg gcatcgtctt agcttactgc aacctctgcc tcctgggctc aagcaattct 57000 ctcgcctcag cctctcaagt atctaggact acaagcatgt gccaccacac ctggttaatt 57060 attgcctttt tttttttttt ttttggagag atggggtttc accatgttgc tttgagtctt 57120 aaggcagatt gctgtctgaa taaaggcaag gaaatataaa atggcctata aataggtagg 57180 taggtaagca ggctggtctc aaactcctgg gctcgatcaa tccacctgcc tcagcctccc 57240 aaagtgctgg gattacagac gtaacccaac atgatggccc aaatcttaat tctttaagcc 57300 attcttcatt agtccttatt gttttcattc tttcatgact attctacaaa atggttttgg 57360 agagaatata ttgatataag ttttatgtgt ttatgtacat ttatttacac acaccctata 57420 tggtacttct tttttggtga catcacattt ggtgatgtac taaggctgat tttactctcc 57480 cattcgctct tttcttctca ttaatatttc taacactgtg attttttgct gaaacttcat 57540 tttctgtaac tgaaaactaa agtactcata ggaagtcaaa aagaaggaaa ttgtctagta 57600 aaataaggaa taattatgat tctaaatgga ccctagtaca ctaattttta cattgtaggc 57660 ttcacttaga tatttactag ctgagaaaag aaatttgcaa accaacaaat tagatattga 57720 gaactaattt tcagccccac aaaaggcaaa taaattcagt ctgacacctg taatggtgaa 57780 agcttaaaat tttaccatta cagttataac attgcaatga aggtggctac acatgcattt 57840 aatgtgtatt ggttatccta ataggtccat tgcacatgat tcaagaattt tggcattcag 57900 aaaactttgt aatattctgt aagtatgtag aagcatcttt ttggtttaaa aaaatagtct 57960 gatacattct agttaaaata ccagccaggt tttgttggta ctgggaaatg ggtacatgaa 58020 gattcattat actctttatt tttgtgtctg tttgaagttt ccataataaa cagttttttg 58080 aaaatcaccc gattaatacc acattcctgg gatctgtatc aaatctaaag tgctggaatt 58140 atacactcaa aaatagaaaa catgtttgtg tgtctgaatc ctctaaaaag aaaaatagtt 58200 agtaatgtta gcatacctca ttgacaatta gatattacct ctcttcaaca gaccagaaca 58260 gaggaagaaa accacttcta tctggttagt gcctactaga tacctttatg tgcaggtcat 58320 ctcagagaac caagaaatgt ttctgctcag atgacttgta aacatggaaa atgtgcctct 58380 ccatatatac cactgcaaga ttctcttggt aaagaacatg taattttata acaacacctg 58440 aaaacgttaa atttattatt cataaatttt ccaagacaca cttcagaaca caagaagctc 58500 acaaaaaaga ttcttactac ttcagttaac atagatacac ccacccctac cccagtattt 58560 gaagaaaaag aaaaaagtct ttctacccct ggtaggcaaa gcaagttatc ccatttgtgt 58620 tttggagtac cagtgctcta ttactataaa gcagtaaagt atcataaggt aataacctcc 58680 tccccgaagg tgtattactg aaaacattta cagaccaata gttcatgaag agaaaatgat 58740 ttattatgtt tttaagagtg gttagtcaaa gttgcatttg tttgttttac agaaggaacc 58800 cagagattga aaaaagttta ttagtagtgt cagaatgaac tgaagaaaaa agaaaataaa 58860 acatagggta gtagtaaggg tgaggaaata tggatatgtg aaacaatata agaacaatta 58920 taaagtacca ccaaagaatg gaaattcaga ttaaaattta tttatgatct tacagccact 58980 ttgcaaaaat agctgtgaaa cagtaaattc atttattact taatatgggg tgtgaaattg 59040 taacaaggca taacatccaa gtgactaaaa gttctttact cattttattg aacaggttta 59100 ttgtgacttc tacttttctc tgtaaggtat taaaaccata ctgcctgttt agatttggtt 59160 cttatccatg gccttattgg tcttattgtc ctgtatgttg caattccggg tttgcaattt 59220 ggttaagttt ttttggaaaa gtcccttaaa aatttagcat gaggattctg taacaataaa 59280 acaaatgtac tttggtgttc cttgaaaatg gcagttcctc ttaagtaaaa atataacttg 59340 catataatgt actgtattca ttcaatttaa attagtatta aataaaatta ttgttttcca 59400 tctctacagt ccattcaaat tacattcata atgagccaga ggattatttt aaattgttta 59460 ttttatcata agactttcct gtggtaggat gcaatcattt agaaaaaaaa aagtactggt 59520 aaataccttg atttttcaat tctaaaactc aatggtagta ttattgatat ttctgttcac 59580 catacacaaa gccagacaaa gtcaagtatg caatattatt cctagttctc caagtaaaca 59640 ttatcctaga aacagtgcag aactttctgt ccatggagtc tgtggccagt catctatact 59700 tcttctcgca tttatttaaa gctttgtctc aatgtgactc ttatcctttc ttggggcgtg 59760 aactctcaat ttccagttca tcatccctat tctggttcca caaacctggt ttctatggta 59820 ccatttaact atttcactta ttattctttt tctgttaaga atctctatta aacaccttcc 59880 aacataagga ataattcatc atgtgaatga agactgtcct caggtttgca gactagcaaa 59940 aaagaattcc tcacccacct tgattctcta ctgccgtgca cttcgtgtca ctccccagtt 60000 ttagatactt cccagggtct cctttcttca gtgtcaaaaa aaaaaaaaaa aagacacaag 60060 aaaattctaa ttggttccac taaaatttag gtattctagc ctaccctaca tcttcatggc 60120 tacatgaaag ctttcatgta ctttttgctg acttttatca acattgttca tgtcagaatt 60180 tctttaatct tctcaagcct tagccaaaca ggctcccaag aggtgattga ctttttattt 60240 ccaggcaaca ttatgatatg aatatcttgg gattgcctct gtattttcac cttttccctt 60300 gtctgttagt tacctctttt aagaaggtac gatttttcct ccttgccagt ctactcgtcc 60360 cacatgtgtt cttttttcca tctcctgttt ccttcaaaac atttttttta atcagttttt 60420 cccactacca tttgcaactt cagtctctcc cactcaacgg gcttattatc caccacctga 60480 aatcaagcac agacattctt ctgtgggggg gaaaatctat ttttttaacc tctttttgct 60540 tcccaaatcc tcaaaattct tgaaagaata ctggatactc attctctcaa attcttacca 60600 tctagtcctt ctttaaccct ctctgatttg gcctctgacc tgttcatgca atgaaaatag 60660 ttgtcttaaa ggtcaccaat gacctttata taccacttat atacatttat tcactcagaa 60720 aatattcatt ttgtgcttgc tatgtaccag gtacttgcta gactaggtac tagaagtaca 60780 tctaaaaaag acaacattct ttttctcaga gaacttataa tttagttgag gaaacaaaca 60840 agtagagaac tacaaagtag tgtaagagtt gcaattaagc atgaggcaac gtgaaagtaa 60900 gaggagcaat gtctaactca gcctttatgt ggtcatagaa gcttttagat agaggcttcc 60960 tttaaaggtt aaggaaaaaa aagatattca ggtaaagaag aaggggaaga gcggtgtttc 61020 taacagaagg tatccttcag aaaggaagct aaaagttaat atgcttttga ttatctgcaa 61080 atttagtaac acaggtacag aattcgttta gggaagtgga tggagataag gcttttacct 61140 gaattgagtt tttaaattta tatttaaatt gttgtgtttg tgtgtatgtg tgtgtgtata 61200 tacgtgtgtg tgtatatatg tgtatatata ggagatggaa aaaatatatg tgtgagtatg 61260 tgttcccact cctcaaaact ttgattatat atatgtatgt gtgtctttta tatattgtgt 61320 gtatgtgtac atatatatac tttttgccca attctcacaa atgaatctgt gacttcaaaa 61380 tataaagaga cactgctata aatgtagttg ggagccaggc gtggtggcac atgcttctag 61440 tcccagctac ttgggaggct gagacgagaa gatagcttga acccaggagt ccagcactgc 61500 ggtaagctat gactgcacca ctgcactcca gcctaggcaa cagaatgaga ccctgtctct 61560 aaaaaataaa ataaatctag ttgaggacca gcttataaaa ggctttgaat accaagctaa 61620 gaagtttttt taaactgtat gttgaagact ctagtttcaa ggattttaag aaatataata 61680 gctcagattt tcatttctgg gaagttaact ttctataatg tgaattatgt aaaggagcaa 61740 aactgcagaa aggggattta ggagacaggt agtagttcag gagtgacatg aatagtgctc 61800 agtgatagaa acaatgcagc tgaagaagag gggatggttc agaaatactt agaaggtagg 61860 atttagattc tagtccacac ttgcccctgg gctcggccct cttgtacagt gcacactctg 61920 cacaaaccta cacagtaccc ccttccaaat gcttatctta ttctggtgga actaagcatt 61980 ctgtgtcaat attggggtac ttgtcttcca catttcaaat tctttgagat tgttgtgtct 62040 ttagattgtc tattccttat agaatctaac agagaattac acatagtaaa cattgaaaaa 62100 ctgtgataat gatgcttaca tagtgtgtgc tctgaaagct tcgtgtatgt taattcattt 62160 aattctcaca accttatgcg atgtgcacta ttattatacc ccctctttgg ctgaattaaa 62220 agaagagtca tggggagatt aaattacttt cctaaggtca cacactagaa agtggtggaa 62280 ctgattcaaa ctgaggcagt ctggctccag agtccgtgct cataaccagt atactaaacc 62340 cattattgga acgcattatt tgaatacact ccagcaattg gtaaatttaa agcaatgtat 62400 aaaatgtttt agtcccacag gattaaaatt aatattttga tttatgtgga atagctaatg 62460 agtttgcttt ctaatctttt tgttttaatc cttttagaac cagttcgaag atacaaaact 62520 tatcatggtg atgtctttag tacctccagt gaaagtccat ctattatttc ctctgaatca 62580 gatttcagac aaggtaggag gcatctgaaa caagcaaact gtttttaaga aaccacgatt 62640 attattattt tcaatagtgt tcaaatatta atataaattg ccagaaagaa taatactgta 62700 taaaattgaa aaatttaaaa aagctgctgg ttactcagta gtagtattat agaaactaaa 62760 tagcagtttc ttcaaataac gatgtagtcc ttttcattac agagataata attcattgtc 62820 tttaaaagta acatgattta cctcaaaaga gtttaataac attatgtcat taattttgtt 62880 ctgtggatta gatttgtaca actctatgtc tgctaagtgt ttgagtttta aatgaaatta 62940 ctctcatgtt tctatcacct gtgccattat ttctttttca ttcataatta gtgagaagaa 63000 gtgaagcctc aaagaggttt gaatccagca gtggtctccc aggggtagat gaaaccttaa 63060 gtcaaggcca gtcacagaga ccgaggtatg tcatgaaaaa gtagtgatga tacatttcca 63120 gtgaccagtg tttgtttttt atttgaatta aatggaattt tttttttttt ttttgagacg 63180 gagtcttgct ctgttgccta agctggagtg cagtggcgca atctcggctc actgcaacct 63240 ccttctccca ggttcacgca attcttttgc ctcagtctcc cgagtagctg ggattacagg 63300 tatgcaccaa tgtgcctggc taatttttga atttttagta gagatggggt ttcaccatat 63360 tggccaggct ggtctcgaac tcctgacctc aagtgatcca cccgcctcag cctcccaaag 63420 tcctgggatt acaggtgtga atcaagtaga atttgttttt ttactatcct ttttccttta 63480 ttttttgcat tttccttttc tcttcctttc ccctagctct ctttgttttt ataaaagttc 63540 tcagaaattc atcaattata tgaaagacaa agtattggaa tcttttaaaa tcatgattgg 63600 ctctaattat ttatagttgt gcttgatttt taaaattatc aatatgaata taaaataaca 63660 ggaaggtcaa ggcatgggat taaaaatctg tgagaagata ggaaaccttg atttctaaga 63720 tacctttctt gaaaggttgg aatagtctca gccagcaagc tttcagtgag tatttatttg 63780 ttgaatgaat agtgagtagg ttactactaa gtaacctatt atgtaaaagg ttaattattc 63840 actgtatctt tcctggctta aaagaggtta tgtggtactt ttttttaaag cctgatttag 63900 gctatttaga gttcattttt atactgacat acttagtgaa tttcttataa ggtgttagta 63960 ttatgtttgt gctcagctta ggatggtggt attatagctg tgtgttgatt tatgttgttt 64020 aaactgaaag gtgtcaagtc aatagtgatg tgtgtctttg tcgtgtatgc ccaggtccct 64080 tacatgaaca aaagatgtag ttaatgctaa gcattaattt caaatttgta atatattaga 64140 gaacaagagg ttgcttgaga atttacttct aaaatgtggg aatcctttct aattctgtat 64200 ttcagtttgt ttaattcaga tgctaccaaa tagaaaagaa tcatttagaa ataaacagaa 64260 acttgcccct tagctaatta attctgccag acactgtttc acacctgtaa actattaata 64320 gatcaggtaa ccctagccat gtgattaaaa cagactattc acagtttaga gtatacgtaa 64380 ttaaatactt tacactaaaa ttattcttta gttaatggtc cacttttttt ttttttgaga 64440 cagagtctcg ctttgctgcc cagactgtaa tgcagtggcg ctatctcagc tcactgcaac 64500 ctctgtctcc caggttcaag cagttctcct gcctcagcct cccgagtagc tgggattgca 64560 ggcacctgcc accatgcccg gctaagtttt gtatattcag tagaggtggg gtttcaccat 64620 tttggccagg ctggtcttga actcctgacg tcaagttatc cacccacctc agcctcccaa 64680 agtgctggga ttacaggtgg gagccactgc acctggccta aaggtccact tttaattaaa 64740 gttgtttctt ttgttttttg tactttttaa aatagtctat aatttttttc tttgaggaaa 64800 actccagtaa gtattcattt acctaaagca atctatattt gcataatagc attttatatt 64860 actgtgtcct tgtgatgacc ccattttgat acttttgaac aaagaggtag gagacaaaga 64920 tctatgcttt acgttacagt tttcttttta ttttttaaca tttattttcg gtttgggggt 64980 acatgtgaag gtttgttata taaacacgtg acaggggttt gtatacatac tattttgtca 65040 agcaggtatt aagcccagta cacaacagtt atcttttttg ttcctctcct tcctcccact 65100 ctccccactc aagtagaccc cagtatcagt tgtttccttc tttgtgttca gaagttctta 65160 tcatttagct cccacttaca agtgagaaca tgtggtattt ggttttctgt tcctgcatta 65220 gtttgctaag gataatagcc tccacctcta tccatgttcc cacaaaagac atgatctcat 65280 tcttttttat ggctgtatag tattccattg tgtatatgta ccacattttc tttatacaat 65340 ctgtcattct gaacatttag gttgattcca ttctttgcta ttgtaaatag tgctgccgtg 65400 aacattcgtg tgtatgtgtc tttacggtag agtgatttat attcctatgg gtatataccc 65460 agtaatggga ttgctgggtc taatggtagt tctgctttta gctctttgag gaatctccat 65520 atcgttttcc acaatgattg aactaatttg ctctcccaac agtgtgtaag tgttcccttt 65580 tctctgcaac ctcgtcagca tctgtaattt ttttactttt taataatagc cattctgact 65640 gttgtgagat ggtatctcat tgtggttctg atttgcattt ctgtaatgat cagtgatatg 65700 aagctttttt caatgcttgt aggctgcatg tatatcttct tttaagggtg tctttcatgt 65760 gctttgccca ctttttaata gagttgtttg tttttctttt gtaaatttaa gttccctgta 65820 gatgctgggt attagacctt tgtcagatgc atagtttgca aatattttat cccattttgt 65880 aggttgtctg tttactctgt ttttctaatg aagcaaaagc atgtggggat gaacaacaaa 65940 agtaagccaa tattgaattg cactaagctc agtgttgaat tgagggagaa tgtgttttag 66000 aagtgacttt tctctatgca tctaatttgg aacctatgag tagttactat tatgcccact 66060 ttagccaatt gaaaactctt gcttttaata taaacaactg aaatagagat aacacctgaa 66120 gaagcactgg gatatgtgtt aacaattgat ttacagccca tttggtttgg atttttaaat 66180 tttaaaacat attcaagcga aattaaatca ttttgggagc cttatgttaa ttttcttgat 66240 aaggaacctc aaaaatgtca aggttatgag agaatcctaa ttttgattgt ttccagattt 66300 tattcaagga aacattaagg ccgccatatt tgtcaaatct atgtttaagg ggtaaactgt 66360 cttttttttc atacttcatg gggagaaaaa gcccatgtgg tattcatagc atctgagtta 66420 gatataggtt taggtgaaag aaaaatattt caggaagtag attgttagtt gtatgtatgt 66480 attatctaat gttaagttgc taaactctat ttcttttaac tagttccatc ttttttctgc 66540 ccacttaaat acatattagc ttaaaatact gtccaaattc ctattcactt gcagaacaca 66600 ctctgataat atccctaaca tgctggtacg taatcaggag tcttgttttc ttctttaggt 66660 cacacatttg taaaatctat gaatagtgct gtatttgtac atattgcatg cttcttgaca 66720 aaagtttcta ttccctttag ctagaataaa atggcaaaac agatccagag agtgctattg 66780 atttgtacca tagtgggatg gggggagatt aacaggaaat tatgagtcag atgcagcaga 66840 atgagtaatt tttttatact gagctatcaa aagcgtcttt cagtgaccaa aaagggcatt 66900 caaagtagtt tccaaagaga atttctaagc ctttttatgt actagctttt gaagtaagtt 66960 tatacgtagt acattcccac tgcttctgtg cctctctgct tgttgaggta acctttgttt 67020 ctgactccaa acagagttgt ttttgttttt gatttttgtc tcaaactttg cagtttttat 67080 agaagttttg gttagatatc atatttggag agataacaat gataattatt ttgctacctt 67140 ttagtagctc tgctgtaaaa taattttagc taaaagactg taatatttta tgaaaataac 67200 aggtttgagt ttaaatgtgc agattcaagg tcttattatt atctttgacc ctccccttaa 67260 gtgagagagg gccataaaat tacattcagt tattgacttt acaggtaatc attgagcacc 67320 tgccatgtac taggtgcttt cagatactgg agatagagtt gtgaacaaca cagaaagtcc 67380 cttgagggaa atgagaagta gccaataaac catgaaaaag caagtaaata atatactgcc 67440 atataatgat ggtgccttga agaaaaataa ggctacttaa ggggataggg agaacgggga 67500 gtaatgtcca aattctgttt tatataggta gtatgatcag tttcattact agaacaagag 67560 gctcctaaca cccaagagac ttcaagggtt ttaggagctc tttgtcagga actggggaca 67620 aagatcatat atgtatttcc ttcccttccc ctctccctct cccccgctcc ctccccctct 67680 ccctccccct ccccttcccc cttccccctt cccctctttt ctcctttcct ctcctctctt 67740 ctgtcaccca ggatggagtg cagtaatacc atcccagctc actgcagcct caaccccctt 67800 acccccaggc tcaatcaatt ctacacctca gcctcctgag tagccaggac tacaggtgtg 67860 tgccaccatg gccagctaat ttgttgtatt tttttgtaga gacagggttt caccatgttg 67920 cccaggctgg tctcgaactc ctggactcaa gcgatccaac cgccttcacc tcccaaagtg 67980 ctgggattgc aggcatgagc caccatgccc agcctatata tttcttcata ccatactgtg 68040 taatgtaaag attcttctga gatgggaaaa taaaatttgt ttaaactctt gcaaccttac 68100 ttaaaatgaa atttgcttga ttagccttaa aacaattgtt ttcctcccaa tcctcacctg 68160 tctcctcttt tctatatagc agacaatatg aaacaccctt tgaaggcaac ttaattaatc 68220 aagagatcat gctaaaacgg caagaggaag aactgatgca gctacaagcc aaaatggccc 68280 ttagacagtc tcggttgagc ctatatccag gagacacaat caaagcgtcc atgcttgaca 68340 tcaccaggga tccgttaaga gaaattgccc tagaaacagc catgactcaa agaaaactga 68400 gggtaagttg attctcaggt tactacacat ctaaacctgc tctcacaggg aactcttggg 68460 caaagtactt ttaaaaattg ctacaggtat ccatctaaag ttacctgtag atgaaactga 68520 aatcccatat tcatttccac tgggattaaa tatctttttg gttgatttta aaataaacat 68580 ttagctattt tcattatttt atctaaaaaa taacttagat gaatttagag tgtcctaact 68640 atatacttta aaagtatatt cataatcctt aaagttaact agctatcttc attattgtgg 68700 gggattattt tttcatatta agaaatttat tattccatat attgagaaga tcagacatgg 68760 aaagttcaag gttaattcca aagttcaaga atgttatcaa gtgcatttca tcttgctgct 68820 ctgtgattct cagaatttta gtaataattc actttctggt taaaagagga ctccattagc 68880 tccaaacatc atatcctcac atttacagta tccaaagaca ggaaggacca agtctgtatc 68940 ttgtatcttg tgggtggata tttttatgta tctgttcttc tagttgatgt atttttcttt 69000 caacctatga caatatattt ttataaacat aaaatcaaaa tgaacagttc ttttctcatg 69060 taaaatatct taaatgtttt acaacttcta cattattgtt agtgttataa aatactttat 69120 tatgtgactt tactgtgtac tgtaatttct ttagtcagtt ccaattactg gacattttaa 69180 atgtttctaa ttagctgttg aaagtaatgc tctaaagcag ggctccacag gccagcattg 69240 gtccatggcc tggtcacagc aggaggtgag caaggagcta gcattgccac ctgagctcca 69300 cctcctgtca gatcagcagc agcactagat tctcacagga gcatgaaccc tgttgtgaac 69360 tgcgttgcat gttccttatg agaatctaat gcctgatgat ctgaggtgga acagtttcat 69420 cccaaaacca tcccctccta cctgtctgtg gaaaaatttt cttccacgga acctgtccct 69480 ggtgccaaaa agatcgggga ccgctgcttt aattaacatc cctgcagcta actcattgca 69540 gataactttc tccaagtaaa atagtcaatt caaaggcaga caccgtttaa gacatttgat 69600 acgtattgtc aaattaccct cccaaaagtt tgtgccagtt tttgcttcct atgatcgtgc 69660 ctgtttcttc atattcttat gtattctgga tattatcatt cttttttact atcatcagct 69720 tgaaaggtga agcaatattt catttgtaac attagtttaa aataattctt aaaaagcaaa 69780 ataaataata gtaaacctgg taaaatctag aatgattttt ttctttttag ttctgcacta 69840 agaaattgta ttaccctata ctgttttcat tttctgttct ttgcttcaga gaattatctt 69900 aaaagcacat ttgtatgctc tgaagataat agaattcaaa tttccttcac agtattctaa 69960 ggagaaaaag ctgttggttg gtgaaaattg cattgaacta caaattggaa gacatgtatt 70020 ctattcctta tgatgctgtt atatgacttt atgtaaattt taaaacctct ttattcctca 70080 ttgtgctaat ttttaaaatg tggaattgga ttgtagttta taaaacacta tccaattttt 70140 aaagttttta gattccaata aaatataact gaacatattt caggtaaaag gaagaaactc 70200 aatagggctt catcaattca ttattaccaa tatctacatc aaaactaagt aataggcagg 70260 atgtcataca atatagtgtg gacttccaat ataataattc agtgaacagc acaaactgca 70320 cgtacatata cacccctttt tcctaaacca cagttttaga gagctaagct agactttggt 70380 tcattcacaa ttcataaatt atagatcgta cctttatagc atgccactgt gatatgtcat 70440 ctcgctaaaa acctgtttcc ttttttaggc agtcaatttc tagctatttc aaaccaaaca 70500 tttctttgcc agagatattt tgtgtcagtg attagataat ttgaactact ggtcattaaa 70560 agactaccta gtattttttc tgaaaagagc tggaggttat atttttgagg ctgaaaaggg 70620 taatggggtt tggaggtaca gtttgaatta atattctttc ccacagcata aatgtttagg 70680 attttttttt cttttggtgc agacacatct taacttcttc ataccctgtt tccatagttg 70740 atctttatta tattctgtgt ttcccatggc agaccacttt cattcttttt tttttattat 70800 tatactttaa gttctagggt acatgtgcac aacatgcagg cttgttatgt aggtagacat 70860 gtgccatgtt ggtttgctgc acccatcaac tcatcattta cattaggtgt ttctcctaat 70920 gctatccctc ccccagcccc ccacccccca acagaacttg gtgtgtgatg tttcccgccc 70980 cgtgtccatg tgttctcatt gttcatttcc cacctatgag tgagaacatg tggtgtttgg 71040 ttttctgtcc ttgtgatagt ttgcttagaa tgatggtttc cagcttcatc catgtctgtg 71100 caaaggacat gaactcatcc tgttttatgg ctgcatagta ttccatggtg tatatgtgcc 71160 acattttctt tattcagtct atcatcgatg gacatttggg ttggtttcat gtcttcgcta 71220 ttgtgaacag tgctgcaata aacatacatg tgcatgtgtc tttatggtag cgtgatttat 71280 aatcctttgg gtatataccc agtaatagga tcgctgggtc aaatggtgtt tctagttcta 71340 gattcttgag taatcgccac actgtcttcc acaaaggttg aactacttta cgctcccacc 71400 aacagtgtaa aagcgttcct atttctccac atcctctcca gcatctgttg tttcctgact 71460 ttttaatgat tgcttttcta actggcatga gatggtatct cattgtggtt ttgatttgca 71520 tttctctgat gaccagtgat gatgagcatt ttttcatgtg tctgttggct gcataaatgt 71580 cttcttttga gaagtgtctg ttcatatcct ttgcctgttt ttcagtgggg ttgtttgttt 71640 gtttcttgta aatttgttga agttctttgt agattctgga tattagcctt ttgtcagatg 71700 ggtagattgc aaaaattttc tcccattctg taggttgcct gttcacgctg atggtagttt 71760 cttttgccat acagacactc tttagtttaa ttagatactg tttgtctatt ttggctttcg 71820 ttgccattgc ttttggtgtg ttagtcatga agtccttacc catccccatg tcctgaatgg 71880 tattgcctag gttttcttct aggattttta tggctttagg tctaacattt aagtccttaa 71940 tccattgtga attaattttt gtataaggtg gaaggaaggg atccagtttc agttttctac 72000 atatggctag ccagttttcc cagcaccatg tattaaatag ggaatccttt ctacatttct 72060 tgtttttgtc aggtttgtca aagatcagtt ggttgtagat gtgtggtgtt atttctgagg 72120 cctctgttct gttccattgg tctatatctc tgttttggta ccagtaccat gctgttttgg 72180 ttactgtaga cttgtagtat agtttgaagt caggtagcat gatgcctcca gctttgctct 72240 ttttgcttag gattgtcttg gctatgtggg ctcttttttg gttccatatg aactttaaag 72300 tagttttttc ttattctggg aagaaagtca ttggtagtct gatggggatg gtattgaatc 72360 tataaattac tttgggcagt atggccattt tcatgatatt gattcctcct atccgtgagc 72420 atggaatttt cttccatttg tgtgtgtctt ttatttcgtt gaacagtggt ttgtagttct 72480 gcttgaagag gtcctttata tcccttgtaa gttgaattcc taggtatttt attttctttg 72540 tagtaattgt gaatgggaat tcactcatga tttggctgtt tgtctgttat tggtgtagag 72600 aaatgtttgt gatttttaca cattgatttt gtatcctgac actttgctga agttgcttat 72660 cagcttaagg agattcgggg ctgagacgat ggggttttct aaatatacaa ttatgtcatc 72720 tgcaaacagg gacaatttga cttcctcttt tcctaattga atacccttta tttctttctc 72780 ttgcctgatt gccctaacca gaacttccaa cactatgttg aataggagtg gtgagagagg 72840 gcatccttgt cttgtgctgg atttcaaagg gaatgcttcc agtttttgtc catttagtat 72900 gatattggct gtgggtttgt cgtaaatagc atttattatt ttgaagtaag ttccaccaat 72960 acctagttta ttgagagttt ttagcatgaa gggctgttta attgtgttaa aggccttttc 73020 tgcatctatt gagataatca tgtggttttt gtagttgttt ctgtttatgt gttgaattac 73080 atttattgat ttgcctatgt tgaaccagcc ttgcatgcca gggatgaagc ccacttgatc 73140 ctggtggata agctttttgg tgtgctgctg gatttggttt gctagtattt tattgaggat 73200 tttcacattg atgttcatca gggatattgg tctaaaattc tctgtttttg ttgtgtctct 73260 gccacacttt ggtatcagga caatgctggc ctcataaaat gagttaggga ggattccctc 73320 tttttctatt cattggaata gtttcagaag gaatggtacc agctcctctt tgtacctctg 73380 gtagaattcg gctgtcagtc tctctggtct tggacttttt ttggttggta ggctattaat 73440 tattgcctca atttcagagc ctgttattgg tctaatcaga gatttgactt cttcatggtt 73500 tagtcttggg agggtgtatg tgtccaggaa ttcatccatt tcttctagat tttctagttt 73560 atttgcatag aggtgtttat agtattctct gatggtagtt tgtatttctg tgggatcgat 73620 gttgatatcc cctttatcgt tttttattgt gtctatttga ttcttctctc ttttcttctt 73680 tattagtctt gctagcagta catcaatttt gttgatcttt tcaaaaaacc agctcctaaa 73740 ttcattgatt tttttgaagg gttttttctg tctctatctc cttcagttct gctctgatct 73800 tagttatttc ttgccttttg ctagcttttg aatttgtttg ctcttgcttc tctagttctt 73860 ttaattgtga tgttagggtg ttgattttat atctttcctg ctttctcttg tgggcattta 73920 gtgctataaa tttccctcta cacactgctt tgaatgtgtc ccagagattc tggtatgttg 73980 tgtcttcgtt ctcattggtt tcaaagaaca tctttatttc tgccttcatt ttgttatata 74040 cccagtagtc attcaggaga aggttgttca gtttccatgc agttgtgcag ttttgagtaa 74100 gtttcttaat cccgagctct aatttgattg cactgtagtc tgagagaccg tttgttgtga 74160 tttctgttct tttacatttg ctgagtagtg ttttacttcc aattatgtgg tcaattttag 74220 aataagtgtg atgtggtgct gagaagaatg tacattctgt tgatttgggg tggtgagttc 74280 tggatatgtc tattaggtcc acttgttgca gagctgagtt taagtcctgg atatccttct 74340 taaccttctg tctccttatc tgtctaatac tgacaatgga gtgttaaagt ctcccattat 74400 tattgtgtgg gagtctaagt ctctttgtag gtctctaagg acttccttta tgaatctggg 74460 tgctcctgta ttgggtgcat atatatttag gatagttagc tcttcttgtt gaattgatcc 74520 ctttaccatt atgtaatggc cttctttgtc tcttttgatc tttgttggtt tacagtttgt 74580 ttcatcagag actaggattg caacccctgc cttttttttt tttttttttt tttttttttt 74640 ttttgctttc catttgcttg gtagatcttc ctatgtccct ttattttgag cctatgtgtt 74700 tctctgcacg tgagatgggt ctcctgaata cagcacactg atgagtcttg actctttatc 74760 caatttgcca gtttgtgtct tttaattggg gcatttagcc catttacatt taaggttaac 74820 attgttatgt gtgaatttga tcctgtcatt atgatgttat ctggttattt tgcctattaa 74880 ttgaggcagt ttcttcctag catcgatggt ctttacaatt tggcatgttt ttgcagtggc 74940 tggtactggt tgttcctatc catgtttagt gcttccttca ggaatttttg taaggcaggc 75000 ctgatggtga caaaatctgt cagcatttgc ttgtctgtaa aggattttat ttccccttca 75060 cttatgaagc ttagtttggc tggatgtgaa attatgggtt gaaaattatt tctttaagaa 75120 tgttgaatat tggcccccac tctcttctgg cttgtagggt ttctgccgag agatcgctgt 75180 tagtctgatg ggcttccctt tgtgggtaac ccgacctttc tctctggctg cccttaccat 75240 tttttccttc atttcaacct tggtgaatct gacaattatg tgtcttggga ttgttcttct 75300 caaggagtat ctttgtggtg ttctctttat ttcctgaatt tgaatgttga cctgcctttc 75360 taggttggag aagttctcct ggataatatc ctgcagagtg ttttccaact tgattccatt 75420 ttccctgtca ctgtcaggta caccaatcag atatagattt ggtcttttca catattccgt 75480 gtttcttgga ggctttgttc gtttcttttt actatttttt ctctaatctt gtcttctcgc 75540 tttatttcat taatttgatc ttcaatcagt gatacccttt cttccacttg atcaaatcag 75600 ctattgaaac ttgtgcatgt gtcacaaagt tcttgtgcca tggttttctg ctccatcagg 75660 tcatttaagg tcttctctac actgtttatt ctagttagcc attcctctaa cctttttgca 75720 aggtttttag cttccttgtg atgggtttga acatgctcct ttagctcaga gaagtttatt 75780 attaccgacc ttctgaagcc tacttctgtc aacttgccaa agtcattctc tgtccagctt 75840 tgttcgtttg ctggtgagga gctgcagtcc tttggaggag aagaagcact ctggttttta 75900 gaattttcag cttttctgct ctgtggtttt atttaccttt ggtctttgat gttggtgacc 75960 tacagatggg gtttggtgta gatgtccttt ttgttgatgt tgatggtatt cctttctgtt 76020 tgttaatttt tcttctaata gtcagatccc tcagctgcag gtctgttgga gtttgctgga 76080 ggtccactcc agaccctgtt tgcctgggta tcaccagtgg atgctgcaga acagcaaata 76140 ttgctgcctg atctttcctc tggaagtttt atcccagagg ggcacccaac cgtatgaggt 76200 gtctgtcagc ctctactggg aggtgtctcc cagttaggct acaggggtca tggacccatt 76260 ctcagagctc aaacgccatg ctgggagaac cactgctctc ttcagagctg tcagacaggg 76320 acatttaagt ctgcagaagt ttctgcttcc ttttgttcag ctatgccctg gccacagagg 76380 tggagtctgt agaggaagca ggccttgctg agctgcggtg ggctccaccc acttcgaggt 76440 tcccagccgt tttgtttacc tactcaagcc tcagcaatgg cagacatccc tcccccgacc 76500 aggctgcagc ctcggaagtt gatctcagat tgctgcgcta gcagtgagca aggcttcgtg 76560 ggtgtgggac ctgctgagcc aggaacggga gaaaatctgg tctgccactt gctaagactg 76620 tgagaaaagt gcagtatttg ggcgggagtg ttccgttttt ccaggtacag tttgtctcag 76680 cttcccttgg ctaggaaagg gaaatccctc tatcccttgg gcttcctggg tgaggtgatg 76740 ccccgtccgg cttcagctca tcctccgatt gctgcaccca ctgtccaacc agtccctgtg 76800 agatgaacca ggtacctcag ttggaaatgc agaaatcacc cgtcttctgt gtcgatcaca 76860 ctgggagctg cagactggag ctgttcctat tcggctatct tccactttca ttctttctac 76920 tctatttcta ttcttgttta aaatgtgtcc tattggttca ttgaatatta ataaacccct 76980 tatgttgaac ttttactttt acataaatgg tatctgtcac atgttacaca ctcaattaaa 77040 ttgaatagaa ttcctacacc aagcaatcag tgagctgtac aaccaaatgc aaagaagaaa 77100 ccaacaaaaa taaaactctg gtaacattca ttagttcaag cacacaccta cacatacaca 77160 cagaccactt gcttctggcc tcaagattag ctctggtttc attctacctt ttgcccatta 77220 agatatgatc tttcagtctt ttctcaaccc ttctcccact cagagtctaa cttgttttaa 77280 gttgtctcct aaactagttc tccctcttag ccaaaacccc agaatataca aaaggagaaa 77340 agggaaatca tagattgaga agcactaaat acagagtttg cactctactt tccccatctc 77400 atgggtcctt tatttcctga aatattttct tgctggggac attggcaggg gtcagagact 77460 atgtgactga tactatccct agttgccact atttaaaacg aaaagtacag tgtcataggg 77520 ttccaagata gtgattacag gtggatatat acatataggc acaaagtaga tgtcttttaa 77580 ctatgaccaa tttttttgtt tttgtctgtt tgcttttaat tttttttaga ggtagggtct 77640 tactttgttg gtgaggctgg agtgtagtgg tgtgattata gctcacagca gcctggaact 77700 catgggcaca agttatcctc tggcctcagc cctctaagca gctgaactac aggtatgcac 77760 cacagtgccc agctaatttt ttattttttg tagaaacagg gtctaactat gttgcccagg 77820 ttggtctgaa actcctggcc tcaagcgatc ctcctgcctt agcctcccaa ggcattggga 77880 ttagttgtga gccagcacac ataccctacg atctgtttta ggctgaatgt cgctttctaa 77940 gacaatgaga ttctgttcaa tcacttcatg cattagcaat attaaaccaa atacttatat 78000 gagctttata actctatatt acttcttcaa gacctttttt ttgagtctga gtctatctgg 78060 atgccaaata gtgaaaaccc tgtaaaacag tgtaaaagtg aggcattatg tttgacatca 78120 atagtagaaa acaaagatgg ggaacaactt gtttcaactt aatgtaaggc atactccatt 78180 tctgttattg gtaaattcca gtatacctct tcatgaaagc ttcaacgttt gttttagatc 78240 acctagttct aatgtggtga ttttgtagtt tcatatgtaa tttattattc ttacattatt 78300 tttcctttca aggaaaaaac tagaataaat agtaaaaaat attgattctg cttatgtgat 78360 ttgcagaatt tctttggccc tgagtttgtg aaaatgacaa ttgaaccatt tatatctttg 78420 gatttgccac ggtctattct tgtaagtaat aaaaccaatt tgtgtcactc ttagaaaata 78480 atttcagtag tgttaaaaac cagttaaaat tcttataatg cttattttaa taaatgccgt 78540 ttattttttc aattgtagac taagaaaggg aagaatgagg ataaccgaag gaaagtaaac 78600 ataatgcttc tgaacgggca aagactggaa ctgacctgtg ataccaaaac tatatgtaaa 78660 gatgtgtttg atatggttgt ggcacatatt ggcttagtag agcatcattt gtttgcttta 78720 gctaccctca aaggtaccaa gacattttat attcagagta cagtatagaa atttagcaac 78780 aagcagactt cctatgtttg ttaccatgcc tgacctcatt ttgacaatta gtaactaaat 78840 gaactagtca gtagaagtga gttaggaact ccctttcttc tcccagctac tttcattgtt 78900 ttaatagtta tgtttgttag gcaccttctg tatctgactg ggaagatttt tttatttttt 78960 gctatggtta tataaaaata tattttaatt atattttagg gaccgtttta tatgttaatg 79020 gtctacatgt gtactctaga aattagtatc ctaatatgag cctgaatgta tagcaagacc 79080 ttatttctga atttccacat cagtttattt agtctactat cctaaaatca cagtgacttt 79140 ttaaaatgtc aattgaaggc taaaaattag ttatttcaca ttatctttta aatattgtat 79200 ccacttaaac ccatgatgtt cacaaccaca gtggtctaag acacagcttc agtagaaact 79260 tctcctattt atcaattaga gttgccatag cagtaagaaa ctttttggaa ttcatctcct 79320 ttttaaataa atcattatat ttataaatta ctctttaata tttcagattc ctgtttacct 79380 caaaatttaa cttggaaagt ttaggcaaca aagtactata aatgacaatt gacaggttaa 79440 aggatcctaa aactctataa gctcttaata tcttctgtat cctaaaagaa atatttccct 79500 caatatagct tattgaatta ttgtgcctta aaaatgaata atttatgctg tagactcata 79560 caataaatag tcaattagta cctactgatg ttctatcact ttactagttt cacttttaga 79620 ctaatcagtc aatattgtct acatgaagct gattcagttc atccaaatat ctatttatac 79680 tatacctaat ttcttacaga ttctggtaaa atcaaattgt attgaataat tcttttattt 79740 gtagagagta aataatagtt aactaatgac attaaaaaat aaaatgataa atgtcattcc 79800 ttctaggttt cagctggtag ctcaataata ataagtatac tagctaatat ttattaaatg 79860 tttaccgtgt actgtgtgct ttaacaagtg tttttattca ttatgtcatt tgatccttat 79920 aacaatgctg taaagcaaga attcccacta gcctgatctt aaagccaaga aaactgatgt 79980 ctagagaggt aaaataatat attcagtgtc atacggatag taaatgttgt gaccaggtgt 80040 tgaatctagg actgtatgtc tttagagccg ccattcttaa aagagtgggc catattgcct 80100 cccatctaaa tggagtgtct cagagctccc tgccacattt ttaacagtct tgtatttata 80160 ttctcatatg atactctttt atgcaagtct gaccaaaaag tgaagaaatc ggaagaaaac 80220 actaaagtat ttttttattt tatctgaata tttttctcat tctgtttaga taatgaatat 80280 ttctttgttg atcctgactt aaaattaacc aaagtggccc cagagggatg gaaagaagaa 80340 ccaaagaaaa agaccaaagc cactgttaat tttactttgt ttttcagaat taaatttttt 80400 atggatgatg ttagtctaat acagtgagta cacaagagtt tctcttttgc tctttttgga 80460 cactggtctt ttgacccttt agcttactga tactgaatta cttgattcca atcaatgata 80520 atgtctgctt tatcataaaa gtaatatttc tttcaacaca gtttatctaa tccttatgcc 80580 ttaaaagctt aataataagc ttagtaataa actcatggaa attaacctta catgcctata 80640 ataaaaacca ccccagtatt caaaatcaaa ggccaagatg tctgtgtgtg tttgtttttt 80700 cagacatact ctgacgtgtc atcagtatta ccttcagctt cgaaaagata ttttggagga 80760 aaggatgcac tgtgatgatg agacttcctt attgctggca tccttggctc tccaggctga 80820 gtatggagat tatcaaccag aggtaggatt tgtgtttttt tccaggacca tttttgtttg 80880 gtgttgttac ctttaacata gttaatgact aaacctgatt caggtgtttg atgtttagat 80940 ctgaagattt ttgaggcttc tttggttcct cagaatgacc aagcactcca tgtatatcaa 81000 ttatataaaa tcatgaagtg tgggattttt ttttcctgtt taaagttatc ctgttttgga 81060 gtttaggaat atctaccact tactccttct cctgagttct aacctataga gactatacac 81120 aggagttatt agtcaaatat aaattaaaag gatctcctgc cttccacatg atgggctggc 81180 agcctggcag agcttactgt gtggagaact cacagtatac ttaaagcctg atgtttctaa 81240 ataaaattga tctaagagga agcaaggggc tagaagctgt gctgctggag cagcatcctt 81300 cacaacgttc atcctaaact agagtgatat gaggcccttg aatgtcacac ttctcaagct 81360 tgctgatcag ttcagtcatt ttatctcact gaatagaaaa gaaagactga tgcatttctt 81420 ctaaaactca ttcctcagag agagaggtag aaatagaagt acttcatctc ttagccaaag 81480 caagaacttt aagatagaag gaaaagggtt tactccaata aaaggcaaac aattgcttat 81540 gaaaacattc ttttatctag gttcatggtg tgtcttactt tagaatggag cactatttgc 81600 ccgccagagt gatggagaaa cttgatttat cctatatcaa agaagagtta cccaaattgc 81660 ataataccta tgtgggagct tctgaaaaag agacagagtt agaattttta aaggtaagca 81720 tccaagatta caaatgataa gctttgtatc ttttccaagt aagcaagaag tgttagagga 81780 cacatatcta agagttcaag tgccagtaac tgatactgtg cataatctca tctcattgct 81840 ggctaaaatt atggtatttt aattctcatt ttgtaaaaga gggaaatgag gctcaaagag 81900 gaaatgtaat gttcccagag atatggggca gatatgattt gaacccatgt ctatctggct 81960 gttaatccta tgcttttatc ttattccata ctcaaaatca aaatacatta tacagaagaa 82020 acaaatgaat ttggtgaatg gcttgatatg agaggcaagt tcatactgat tctagaattg 82080 tttgttttgc tttttctcaa aaggcttaaa attcaattac atcctttaaa aatggtcttc 82140 ccactaaatg ccaattaatg tagatagggg tagagagtca caaaaattga cttattagtt 82200 tacagttcta ttagttctac agtctattag acctataacc agctttctat atgaccttag 82260 ataaatagta catttacgat caagaaaaat agtattatgt aaacttccaa tgcaaatagc 82320 aaatataaga tagtgttctg ttgaaaagac aaattttcag aacattcttc tgttttagct 82380 tcctaggatg taacagtatg ccttccattc actgctgcat atagaaagaa atcaagttta 82440 ccagccctgt gaaaatttat gaagggattt tattcacaga cttacattac ctttaatcta 82500 gtgttcatgg aaagaaagaa aggcaaggtg gttttttctg tttgagtcca aatttaaaga 82560 tattaaatta tggacttata cttttcttag ttattacatt tttatacttg tagaaagtaa 82620 gatgttacat tataatttta ttaataaagg tagaaggcag attggcacag tgaaaagaat 82680 ttgcatgagg atttgcagac agacagtctt gcatttgaat tcttatttca actagctgag 82740 tgaccttgaa caatgtgttt aacttctcta agtctcagtt ttctccttgt aaatagcatg 82800 cctaaggaat attaggttgc cctactcctt ctaataatat attctgttac ttcatttcac 82860 tttaacttta gcatctttct tctaacttaa gaagttttat cttgttaaca caaccttcta 82920 aggctacact tttgctatat attatgttgt ttttgaaata tctttcgtaa atctgcttta 82980 ttgcagtata atttacatac aataaaattt accattttta agtgtttggt gagtttttaa 83040 aatatatgtg cagttgagct gggcatagtt agggatgcat gcctgtaatc ccagctggtt 83100 gggaggctga tgtaggatca cttgagcctg ggagtttgag gctgcagtaa gctttgatct 83160 tgtcactggg ttccagccta agtaacagaa caagacccca tctcaaataa aataaaataa 83220 aatataaaat aaaataaaat aaaagtaaaa aattagtata ataaaatata aaaatatgta 83280 tacagttcag caatcacctc cacagtcttg agaacaaggg ttagcaaact gtggcctgcc 83340 tgttttgtaa atagttttat tggaactagt ccatactcat ttctttatat atcatctatg 83400 tctgcattca tactataaca gcaaagtcca gtcataacaa taaagatcat atgacccaca 83460 aagactagtc catactcatt tctttatata tcatctatgt ctgcattcat actataacag 83520 caaagtccag tcataacaat aaagatcata tgacccacaa agcctgaaat atttactatc 83580 tggcccttta cagaaaagtt taccaactcc tgatacagca catttcgaat acataaagct 83640 ccctcttgtc tctttatagt cagtcccctc cccctacctg taatccttag caactactga 83700 tctgctatta ccatagtgtt tttttttttc taaaatgtca tgtaaaaaat aatataatat 83760 acagtctttt atgtctggct tctttcactt agaataatac ttttttttgt ttctgagaca 83820 gagtctcact ctgttgccag gtaggagtgc agtggcatga tctcggctca ctgcaacctc 83880 tgcctcccgg gttcaaacat tctcctgcct cagcctctca agtagctggg actacaggca 83940 catgccacca cgcctggcta attttttata tttttagcag agacatggtt tcaccatgtt 84000 agccaggatg gtctcgatct cttgaccttg tgatccgccc accttggcct cccaaagtgc 84060 tgggatacag gtgtgagcta ctgtgcctgg cctagaataa tacttttaag attcatccat 84120 ggtgtggtat atatcagtag tttcttttct tttttttttc tgagtagttt ttctttgtgc 84180 agatacataa tttgcttatt cttttcatta gttgatagat ataaagctgt tataaacatt 84240 ccagttcaca tttttctgtg aacacagttt ttatttctcc tgagtaaata tctagcagta 84300 ggattgctgg gacctatggc aagtgcatgt ttaactttgt aagaaacttc caaactgttt 84360 tccaaaatca ttgtacagtt ttacagtcct accaacagtg tgtgaatttc agttgctcca 84420 catccttgac aacacttggt agtttcagtc tttttcactt taacatttga aataggtgaa 84480 tagtggtata ttattatggt ttatatattt gtacttccct cattactatt tatgttgacc 84540 aatcttttca tgtgtttatt tgccatttat atatcatctt tattgatgtg tcaaataaaa 84600 ctttttaccc cctttttgaa cctggttata tgtnttcctt actggtaaga agtacatgtt 84660 ctttaaatat tctggataca agtcttttat cagatatgtg ggttttacat atatttattt 84720 actcctagtc tgtggcttgc cttacatttt cttaacattg actctttttt ttaagagtct 84780 cactctgttg cccaggctgg aattcagtgg tgcgatcttg gctcactgca gcctccacct 84840 cccaggctca agtgatgctt cttcctcagc ctcctgagta gctgggatta tagatgtgca 84900 ccaccatacc tggctaattt ttgtattttt catagggaca ggattttgtc atgatggcca 84960 ggctggtctc aaactcctag cctgaagtaa tctgcctgcc ttggcctccc aaagtgctga 85020 gattacaggc ataagccact gtgccagcca acattaactc ttgatgagca agttttcaat 85080 gttaatgaag tttccaattt tttttatttt ctagtttatg gtttttgtgt tccatctaag 85140 aaatttttgc ccaacccagg gtcacagaca ccttctaagt tttatgcttt tagtgcctgt 85200 atttaggtct gtggtccatt tttggttaaa tttcatgtgt agggtgaagt aagggttgaa 85260 attcattttt ttagcatgtg gatatacagt tgtcccagta acctttgttt aaaagattat 85320 cctttccaca ttaaactaca ttgatatagt gtgttagtcc tttgtcacac tgctgataaa 85380 gacatatacc cgagactggg caatttacaa aagaaacagg tttaatggac ttatagttcc 85440 atgtggctgg ggaggcctca caatcacggt ggaaggtctc acatggcagc agacaagaga 85500 agagagcttg tacagggaaa ctcccctcct taaaaccatc agatctcgtg agacttactc 85560 actatcatga gaacagcatg ggaaagacct gtccccatga ttcacttacc tcccactggg 85620 tccctccttc aacatgtgga aattcaagat gagatttggg tgaggacaca gccaaaccat 85680 attccacttc tggcccctcc caaatctcat gtcctcacat ttcaaaacca atcatgcctt 85740 cccaacagtt ctccaaagtc ttaattcatt tcagcattaa cccaaaagtc cacagtccaa 85800 agtctcatct gagataaggc aagtcccttc tgcctatgag cctgcaaaat caaaagcaag 85860 ttagttactt cctaggtaca atgggggtta caggcattgg gtaaatacag ccattccaaa 85920 tgggagaaat tagccaaaac aaaggggcta tacaggtccc acgcaagtct gaaatccagc 85980 agggcaggca aaccttaaag ctgcaaaatg atctcctttg actgcatgtc tcacatccgg 86040 gtcaagctga tgcaagaggt gggctcccaa ggtcttgggc agctctgccc ctgtgtcttt 86100 gtagggtata gacccctcct ggctggtttc atgggctggt gttgagtatc tgtggctttt 86160 ccaggtgcat ggtgcaagct gtcgttggat ctaccattct ggggtctgga ggacagtggc 86220 cctcttctca cagctccact aagtggtgct ccagttggca ctctgtgtgc aggctccaac 86280 cccacatttc ccttccctac tgccctatca caggttctcc attagggccc tgcccctgca 86340 gcaaacttct ccctgggatc caggcatttc catacatcct ctgaaatcta ggcgaaggtt 86400 cccagacctc agttcttgac ttctctgcac tcacaggctc aacaccatgt ggaagctgcc 86460 aaggcttggg gcttccagcc tctgaaacaa cagcctgagc tgtaccttgg ccccttttag 86520 tcatagctgg agtggctggg acacagggca ccaagtccct agactctaca cagcagaggg 86580 accctgggcc cggcccacaa aaccattttt tcctcctaaa cctccaggcc tgcaatggga 86640 ggggctgctg caaaggtctc tgacatgccc tggaaacctt ttccccattg tcttggtgat 86700 taacatttgg ctccttgtta cttatgtaaa tttctgcagc cagcttgaat tttgcctcag 86760 aaaatggaat tttctttcta tcacattgtc aggctgcaca ttttccaaac tgttatgccc 86820 tgtttccctt ttaaaactga acgcctttaa cagcacccaa gtcacatatt gaatgctttg 86880 ctgcttagaa atttcttcca caagataccc taaatcatct ctctcaagtt gaaagttcca 86940 caaatctcta gggaaagggc aaaatgctgc caatctcttt gcaaaaaaaa aagaaaaaga 87000 aaaagaaaat aacaagagtc acctctgctc cagttcccaa caagttccca acaagttcct 87060 catctccatc tgagaccacc tcagcctgga ccttattgtt catatcacta tcagcatttt 87120 tgtcaaagcc attcaactag tctttagaaa gttccaaact ttcccacatt ttcctgtctt 87180 cttctgagcc ctccaaactg tttcagcctc tgcctgttac ccagttccaa agtcacttcc 87240 acatcttcag gtatcttttc agccatgccc actctactgg taccaatcta ctgtattagt 87300 ccattttcac actgctgata aagacatacc tgagacaggg caatttgcaa aagagagagc 87360 tttaatggac ttacagttcc atgtgactga ggaggcctca caatcatggc agaaggtgaa 87420 aggcatgtct cacatggagg cagacaagag aagagagctt gtacagagaa actccccttt 87480 taaaaccatc agatcttatg agacttattc actgtcacaa gaacaacaca ggaaagacct 87540 gcccccatga ttcagttacc tctcagtggg tctctcccat aacatgtggg aattcaagat 87600 gagatttgtg gggggacacg gccaaaccat atcatacagc ttcaatatct ttatgtcacc 87660 atttaccaaa gtgtattgct atggtatggt attattccaa caggtctgcc aaagactgac 87720 agaatatgga gttcattttc accgagtgca ccctgagaag aagtcacaaa caggaatatt 87780 gcttggagtc tgttctaaag gtgtccttgt gtttgaagtt cacaatggag tgcgcacatt 87840 ggtccttcgc tttccatgga gggaaaccaa gaaaatatct ttttctgtat gtccatttaa 87900 cctcttttca ttatattttc aaatgatatt accaacttcc aatgtaacat attaacagac 87960 tttccttaga ctctgccatt cagtggggat aatacatctt aatactattt aactcttcct 88020 ttgtagttgt ggaaattatt attgagattt tatttatgtc tggttttttc aacaggtgac 88080 ttttaagatt attacacatt cctggctggt tatatgctca attaacttta gttaaattac 88140 aaccaagttg aattctctga ataagtcaga atttattcta gggttgtaac ttctcacatg 88200 gagaaatcct cctaatgttt ttaagaaaga tagttatctt aaccctagtg aaccttgtct 88260 ggcccaatag taaaccccct cgtagcaact gttatttgaa tctcagaggt acagagactt 88320 actggatttt atgaactagt cccaggactt tccgcaattt tagattttta gtgtacagct 88380 ctctataaag ttagaaaatg atttttagaa aataatatgt ttatggaaga tagttagtga 88440 taaaggcata ttttgatttt ggacctagtt gggacacctg aacattaaag ttccattggc 88500 agacttcaga gatgaataaa aaatattaat atgttcaggt gtttgttttc ctagtgctat 88560 tcaggaacta ctgatacctt tagttcatct ttaggctaaa gtatagtctc agcaaaacag 88620 tatttataaa gttaccaagg tcctgatgga tctggataat cttcaaccct gagaccattc 88680 ctagacctaa tggttagttg attggcttcc tctgaaacca agagatatca ctaagatttc 88740 cagattatat gttctccaga ccacccacat cttctcaaga ttgtcaggac caagaaatta 88800 cctgggttta acttaccttc ccccagtgga aatgctggca gagcccatgt ctgaaggaaa 88860 ccttagattg attaattata aatccagttt tggaccgttt tgaaaaggtg acaagtcaaa 88920 taatcacaca gcagtcaact ctatgtaatt tgccaagcta ccacactaac ccacatatat 88980 agaacgagct gtgattagtt catttttaaa gatttgtggg aatagagaat agtttgcatt 89040 cccatggaaa ttattcctat atttaatagc attcattttt cctgaagttc tttctctaac 89100 acaaaactat tttttttaac tctccttttt tcttctacta acctctgggg aagtggaaaa 89160 gttactattt ggtcttctca tatctcacaa ctgagttctc tcaagcacat ttcttatcca 89220 gtccatccat taacacttgg agagaatcaa atattctttg tatgtgtttc aagactatac 89280 atctttctta gatattaaat catctatact atcacttttc ataattaata tgaacctcta 89340 acctatctct ggcatttttt gtgtgtgata tttgctgcct ttgggtgttt tattataggt 89400 agtggttctg tagttctttt gactgatcaa ctaagaagat tctttctttc atgtttatgc 89460 ttgaatcagt gagagagttt tacaactatg gagttcagtg tctttgcaaa ttccttgaca 89520 gtggttaagt ggcatgtttg ttaggggaaa aaaaaaatgt tctccaagta tttgaagagt 89580 taccaggtat actactgata atgaagatac tagtttgttg ctactgtatc tttagctcct 89640 ctctaatact tactaatttc tgtttctaac aaagaaaaca ggtttaatcc tggagctttc 89700 attggcaaca atatctagct agaatttaac aatgttgtta tatttctaaa atttctttga 89760 atttatataa ataagaaaag tccattgaaa aatttataaa taaccaaggc tagaaattgt 89820 aaagatgaca ggattgaagt ctgggtaata ctctgttatt acaacttttg aaagcctact 89880 aaatttggct tttccatgac tatttccgta tttgaagtaa agacaaggaa catgaagtag 89940 aataatctgc acagtagcca agagctagag tacagtctaa ctggacttaa gtggttctcc 90000 agagacatta gtcttagatc cccgacatgt tgaacactgg tctcttaagg catgggtcac 90060 cagcaagcct taccatatag gtcacaaatt ggagtatgct ctcttccaca aaagacattc 90120 agttttcaag aaatttcaga gtgataaaac tgatttgatg attctcctac tttctctata 90180 tttggcacaa atcaccatct ctaaatatca atgtgtttta tctctcaacc cagcagttat 90240 gttaccagta cctttccatc tcacattttc tttaattttc cacaacttct attcagcctt 90300 tatgccaccc agactctact tgactgaatc ctggctctta tcattatata ttaataaaaa 90360 aattattgtt aaactttcat tttcttgtat ccaatagagt agaacacata tttattattt 90420 ccttttcaaa cagttttggt gtttgtaaac attaccataa attcaaaata tcaataatct 90480 tatcaaagga atctgtttcc cttgttaatg actgatatat acaatctaga tttaggctac 90540 aatttctgaa agtggcaaac gatgttaatt tatttcttgc atttgtttat aataatacag 90600 tcatgtgcca tgtaacgatt tttcagtcaa caactgacca cgagcaatgg tggtcccata 90660 agattataat gttgtatctt taccacacct tttctgtgtt tagatgtata ctacacaaac 90720 aattgcctac agtatttagt acagtagtat gctgtacagg tttgaaacct aggagcaata 90780 ggctacatca tatagcctag gtgtgtagta gtaagctagc ccatctaagt ttgtttaagt 90840 acacttcagg atgtttgcac aatgacaaaa tcgcctcatg atgtatttct tggaacatgt 90900 ctttattgtt aagtgatgca tgactatata ggattatatt catattagat gtaagtcaat 90960 atccagtgcc taacaagaaa tataaataat atctctactt actataatta tgaataccct 91020 tggttaatat tgtagaaaaa gaaaatcaca ttgcaaaata catcagatgg aataaaacat 91080 ggcttccaga cagacaacag taagatatgc cagtacctgc tgcacctctg ctcttaccag 91140 cataagttcc agctacagat gagagcaaga cagagcaacc aagatgccca agatattggt 91200 aaggagaagc agactatttc agatgactcc tgggaatatg aataattttt gccaccaagt 91260 tttaaaagaa ctgccatgat taggatgaaa acttacaatg tatatacatg ttaaatagct 91320 aaatcaagtc tataaaggtg ttacaagtga agccaatatt tcaatttcat gttcaccctg 91380 agagaatact cctagggagt acctgttgaa gtgtccattt tgtgcttagc aatgataggc 91440 tagttgatgt aaacattata aacatttggg ccatgttctc taccctcagt aagcttatcc 91500 aatatttgga agggtaagac caacatgctt gaaacagcaa tacacaatag aagttcagga 91560 tttcagccag gcacagtggc tcacgcctgt aatcctagca ctttgggagg ctgaggcggg 91620 tggatcacga ggtcaggagt ttgagaacag cctggcaaac atggtgaaac cctgtctcta 91680 ctaaaaatac aaaaaatcag ccaggcgtgt tgccgggcac ctgtaatccc agctacttgg 91740 gaggctgagg caggagaatc acttgaacct gggaggcgga ggttgcagtg agctgaggtc 91800 gcaccattgc actccaacct gggcgacagt gcgagactct gtctcaaaaa aaaaaaattc 91860 aggatttgaa gaacagatta tattgaacag actttatgac ctatactgtt agaagaggga 91920 aatcagagac tagagtactg gacaggtggc acttgaattg gatataaagg ataaaaataa 91980 tgcaagtagt ttggagataa atggaagggc tttagagatg agggaaaaaa cacaggaaac 92040 aaggcagagg atgggggaag tatgcaccca gaacaggaca gtgaagagac acactgtata 92100 gtcttctggg tggcagattt actacctatt agttttactt gggtgcatcc ctgttctgag 92160 attgagatga ataatcatag tacccaatgt aaatggtcag gagaatggtt tattttcttt 92220 tgaaaaggag ccagcagaag aaactcatct gactctggaa aaaatatctc aatcagaact 92280 gaaatattta aatttcagag agataaaact gatttggtga tttctgcaat tagagattaa 92340 aattatacaa aatctaattc tacatagtaa attcttatag gtataagtga aacagtcaga 92400 agtatgtgat ttaaaaattt aatggaatag cactgatgac cttgtgcagc agggtcctat 92460 gaattcttta cccaaactgt ttcacattca aaaaatgttt tccccataag ggcagactgg 92520 ggcgatggca acctatgact agatgtttct caacctttca gaatcatgat aggggtggag 92580 gttgtatgct gatttaaaat gaagattcca ggaacctacg taaaactcag agagctacag 92640 tctttgggaa tttgttccct aaaatctgta ctttaacagg ctttcctcag taatgttttt 92700 ttttgttttg ttttttcttt tatttgatac ggagtttcgc tcttgtcaaa atcttgtttg 92760 ggtgcaatct tggctcactg caacattcgc cttctggttt caagcgattt tcctgcctca 92820 gcctccagac taggggatta caggcacccg ccaccacgcc cagctaattt ttgtattttt 92880 agtagagacg gggtttcact atgttggcca ggctggtctc aaactcctga ccttcgtgat 92940 ctgcctgcct cggcctccca actcagtaat gatttttaca catgctaaaa tacaataacc 93000 actgctataa tatcattatt ctctttctgc tttgctctgc tagaaagttt atatgctcat 93060 atattttcaa agtatagtga aatatcagac ctattagagc catcagcatt cttactttga 93120 ctaatattct attcagtaca atccataaca actgaagatt acttcattat agttgttgta 93180 tagtgaacag aatcagaaga caaaagtttg aagttagtct gtcatcctca acatttctta 93240 tactgaagaa caatatggta tagcagttaa gagcatgagc tcaggagcca aattgccagt 93300 ggcaaattag gctctgtcac ttacaagccc taaaactttg ggcaagctac ttaaactctt 93360 tgccttagtt actttatcta tagaatgatt gccataagat aatacctata tcagaaagtt 93420 gtgaaaagga aatgaattca tacgtgtaga atcctttaaa actacctggc acaaagtatt 93480 cagtaaatat ttactgaagt attcattatc attgtcatca ccatcatcaa caatgtttta 93540 cctctagaag atagtactac tactatacta tatgctgcta tactatgtaa tagcggtaat 93600 agtagcagca gcagcagcgg cagcagcagc agcagcagca gcagcagcag cagtagtagt 93660 agtagatgaa tgaatgacct taggaaagta agtgactttt tagaatctca gtttcttcat 93720 ccatggagtg gggctgggaa taatgttgta tatatagata taacaggttt acccccagga 93780 tcacaacagc tatgtatcct tgccctcaaa agtgaaagca ctttaagatg gtgtgatcta 93840 tatttttccc cttggcttat aagtaactgt ctgcctgttt atttgtacta caagtgaaaa 93900 caactggtgt tatctgtggg cggttaatgg gctaacaaat gtatgctgct tctttagagt 93960 catagaatat tgatgctaga aagaacctta caggtcatta agttcaaaat tttactaatg 94020 gcaaaacagg ttcagagaag atagtgtttt gccctcatgt catatataga ggtctcttaa 94080 ttcctaatcc agggtacttt ctgtttgatg agtttcccaa gaactgattt gcatggattt 94140 aagattaatc aattattgag catttactat ttataagtgc acactactat gggataagag 94200 aataaatgaa gtccctctca taaaaagaga atatgattaa gctggagata taaggaagca 94260 caaaatggta ccagggactg aacaatagca gaaacagatt aggaagtatg gattgcagac 94320 agtgtggagc tagcgagcct ttgtgttcaa atttgaaaca ttagtattag gatacaggct 94380 cattctaatc tatgttggag ttctttccag gtaaaaggca gtaggaaaga ccagataaat 94440 ggttggttta tgatcccatc ccatatccaa gagtaggcta caaatggatt tgaatagcat 94500 actccctaat atgttcacaa aactgactaa actgagcctg ctatccttat tcctgccaaa 94560 gtttggtcca cattttcttt aaggatggag aaacctattg ggtgtaaagg catttccttc 94620 tgaagacttt attttgcttc tttgattaca ggctactcgt aaagtaaatg aaaatagaat 94680 agcattattt gctctaataa aaactatatt ttgaggtaaa gatgattatg gaaatttttt 94740 tttttaatgt agtatcgctc tgttgctcag gctggagtgc agtggcgcga tctcagctca 94800 ctgcaagctc tacctcccgg gttcacgcca ttctcctgcc tcagcctccc aagtagctgg 94860 gactacaggc gcctgccacc acgcccagct aattttttgt atttttagta gagatggggt 94920 ttcaccgtgt tagccaggat gatctcgatc tcctgacctc atgatccgcc cacctcagcc 94980 tcccaaagtg ctgggattac aggcgtgagc cactgcgccc agcctgatta tgggaatttt 95040 taacaaaggt gtatttttaa aagtctttgt tttttaaggt cttgttataa cttggtgccc 95100 acttccactt cagagagaga tcattgaatt ttcctagtga caatgaggca tgtttcttta 95160 aacttcattc tgatgcatga atattaaaaa cctttaatgt tttcctacct ctttatgcct 95220 gagagaaaat atcaattatt aatcttccta ggaagtagaa gataaatgaa acaatccaag 95280 aatctaagtc agtaatcatt tgatattttc tttcttcctt ctcccctccc tccctcctcc 95340 tctgtctcct cttcctcctc ctcctccttt ttcttcatct tcatcatcat catcatcatc 95400 atcatcatca cctggcaccc ttgagggaga cattttcttt ataaaaggaa gttttcccag 95460 ttgttgtatg tagcagtcaa acttagttct gtgtagaatg caacaacata gaattgctgc 95520 tttccagagg gcatcaaagg gagtgccttg tgatgtgggt cactaactgc atgaaaaact 95580 aaatcatttg aaatcctttg ctcctattct tcatttacat atgctgcatt gcttttgtta 95640 ttagcctcaa atattaaaat atcactgtga cattggttcc tacaaaatag aatagccaaa 95700 cacttgttat aaagtatctg taaatttagc ctctataaga gaactttgga tgtgtatttg 95760 ggagtgaaag aaattgaagc ataaagagat gcccagctcc ctgatcatgt taatttacag 95820 atactgaaac agacagatta gtactgtttg attctcccat tcctctgttg cctcagataa 95880 atccttaagt cagcccagtg agaaggtggg tttggcatag tagtgaaata acaaaaggaa 95940 taatttgcca taaatgcttt ttctttgtaa cagcattatt gagatacaat tcaataccat 96000 acattcatcc atttaaagta tgcaattcac catcaccgca atctgcctta agctttaaaa 96060 actgtctggg caaaacccct ctgcatagct ttttcaggtg tgtattcacc atctcagccc 96120 atctaggttt cgtctctccc tctccctatc cttgggtgct gatattttag cagagacagt 96180 actaggtttg aaaatttctg tgttaaatgt cattctcatt tctaactgaa acctataagg 96240 aatttggtgt cagcaagcct gagccccaaa cattgttgag tccaagaaaa tcattagatg 96300 aagcaggaaa tgttgagtag gctgcaacta agagaaagct aaagagatga aaatatgtta 96360 tgaaaaccag atcttcaacc ctccttttta aaaccctgat tgccacactt tgaaagctac 96420 ctacttatgc tggcaatcaa aatgattaaa aactgcatgc tgcttattta ttaacataat 96480 tattctcata aaagtactgt ggcgttacca tcatgtaaag caatcctatt tccttgtaga 96540 gagagcttcg tttaggagcc tgaatctcca agcagagtct gttagaggat ttaatatggg 96600 acgagcaatc agcactggca gtctggccag cagcaccctc aacaaacttg ctgttcgacc 96660 tttatcagtt caagctgaga ttctgaagag gctatcctgc tcagagctgt cgctttacca 96720 gccattgcaa aacagttcaa aagagaagaa tgacaaagct tcatgggagg aaaagcctag 96780 agagatgagt aaatcatacc atgatctcag tcaggcctct ctctatccac atcggaaaaa 96840 tgtcattgtt aacatggaac ccccaccaca aaccgttgca gagttggtgg gaaaaccttc 96900 tcaccagatg tcaagatctg atgcagaatc tttggcagga gtgacaaaac ttaataagta 96960 agaacatatt aactaaccca attacatatt tgtaaattct acatttcata cgtttctttt 97020 tgttatgaca ttttattatt ttcaccatat ttttttacat taacacttcc ctcctacctt 97080 ccttttccct cttcagttca aagtctgttg cgagtttaaa tagaagtcct gaaaggagga 97140 aacatgaatc agactcctca tccattgaag accctgggca agcatatgtt ctaggtcagc 97200 aaaaacaagc ttaccttctt tgtcccatac ctcatgctca gagggaagtg aacaagatca 97260 tcttaattat caaattattt tgggttccat gtcctaattg ccaaaactga atataaattt 97320 taggctactt aaaatgcacc aaatcaaatt accacttgat ttaacaagtg attgcttcat 97380 ggtacagact attagcttct ctttttttcc ccctcagaca gggtcttact ctgtcaccca 97440 gtctggagtg cagagatcat ggctcactgc agctgcaaac tcctgggccc aagtgatccc 97500 cccacctcag cctcctgaat agctgtgact acaggaacgc agtaccacat ctggcttttt 97560 atattttttt gtagagacag ggtttcacta tgttgcccag gttggtcttg aactcctgga 97620 ctcaaggggt ctgcccacct tggcctccca aagtgctgag attacaggct tgagccatca 97680 cgcccagtct gttagcttct cttggtcaca gttgccatga cagtcttact aagactgtca 97740 tgtgccatta ctttggatta ccttttttgg cttttccttt caagccgatg tgaatgaact 97800 ctggtaatgc tatagttttg gagaagcatt tacttagaat gctttcagct tagcaggaac 97860 aaaattgtct ctaaaacctt agataatttt atgaaatgtg ctatggttga taggtagaag 97920 tttttaagtt gatttcagtt tcttcaaatt ctcccagata gcagggcata ttatttaagt 97980 gaaattgtat gtatgtgtgt gtgtgtgtgt gtgtgcatgc acatgtgcat atatatctat 98040 atatatgcac cttttaagat gcttaccttt tatacatgct accttttaag ataaatagtt 98100 caggtttcct gttgccttgt gcaacttaaa agggaaacgc actggagtcg atctttgaaa 98160 agaatggatg tttaagcaca gagatctgaa ctactactca aaatatgaaa cagcgtggga 98220 aacaaaaggg aaatgaggac tgtttccctt ctgttgtctt acgaaatact actaaactct 98280 cttcttaggc tcaaggtttg ttaatttatc tctaattacc caaagtttaa aagctttttt 98340 tattctataa ttggattcag ggtatgtcga gtaaatgaag acaaaagaca attctgcatt 98400 ataatacata aatatttatg gaagcaacat tactttatta atgtaggctt tcgcaacttt 98460 cagagactat actatcaatt taatttcagt cagttaaaaa aacttagata aaaggcaaga 98520 tttcattcta taggtaactc tgtgttgaaa ataggctaag agattgattt gatcttttag 98580 gaaatacttt tcaaagtgtt cacatataac ggggcctcat acattctaaa ctattttcat 98640 taagaaggct ttggtctaca tgaaaattca ttacatatcc gaaggaaaat agtaaatact 98700 ctatagaaaa cataaaacac tcttaaagga aatttttctg cattttgtat ttattcattc 98760 ttactgaata atgaatattc ttttaacact tgaacaaatg aaaaactcat tccagtttca 98820 tcatttcata tttgatatat caaagtattg tcagaaacaa tatatttgtg tttaaattta 98880 tgctgcaaaa taagttatta tgcttagcta ctatttaaaa tagtgaaaat gcccattgga 98940 ggatgttttc tcagtgtaaa tacaaaatgt tgctgcctta ttgttctatt gatttttatg 99000 agcttatcag aagaaatcac ttcgatatct agcatctgac catcttatga aatgtctaat 99060 atttaattta tgccacagga atgactatgc atagttctgg aaactcttca tcccaagtac 99120 ccttaaaaga aaatggtagg tttacaaaat gtttttcccc tcatttccat catttcttgt 99180 accttactga gatagtcttg gacctaacaa tgaagagtct tgagttccat gcctaggatt 99240 tgatcttaca ttgaagttaa aggagagttg tatttttcag catcataatg atgtaatggg 99300 acctctgatt taggctaatg ttgatgaaat gacaaattag agataaggac actaattggg 99360 aagctaagat aatagttcag gtgggagata atttctatta aaaagagttt taactgaggc 99420 agttatttta aagggatgct ggagctgaat tttagaggga aaggaggatt cattcagacg 99480 gaacaataaa gataagcatt ccagatcaag ggcatagcat ggtcagagac atggaatcat 99540 gagaaaagaa atttagggaa ctgcaggagt ctcagtatgg tggcatgtgg gggccagggt 99600 aaagtttgag aactaagtag ggaccagttt ttaatcttat gctaaatatt atgaggatat 99660 tttgaagact ttaaatgctg agattatagt ttagaaggaa tctaagaaac aaaatcgtag 99720 gcagaagacc agaaatgtcc agtgacttga acatcactgg ctttaaaatt tttagaattt 99780 agattgcaaa gtattttcat atacattatc ttatttgatc tttctaacaa ctttcatgag 99840 tagaaaataa tgttttatta ctatccatac actactttcc tccaaaaatg tttcagtctt 99900 ggactcttaa agttgaaata attaaaagcc tgatgagaaa gaagccatta tgttaattaa 99960 aattattaat acagctaaac ttgatgaagt tgtaaattta gtttcaatat tcctgtagcc 100020 agggtaaaac agaaggcata agactgaact atatagaatt gctgggtatt tttaggtcaa 100080 aactgtcaaa caccagagtg ctattttgta tgattctcat tctctaataa aaatacacat 100140 actaattctt taagacagaa aaaattttct tggaattaaa attgctttta aaagtaaaac 100200 tacacacaat gtcttaaata ctcatagcaa atcaagatga ggtttctttc cttctcattt 100260 tatttttgaa tgtatcctcg aaaaatatga gggcctatca ttaaagaaaa aattattgaa 100320 cttatacttg gacgtaaatt gctaatcctg ttatatagct ttctagtgat caaactcctt 100380 acatggactg aatttagaat gcctatatac ctgaaatacc ttagttatta acatgtccat 100440 atggtagtaa ttattgacta acagttattt agtgcttact atgtgtcaag cactgttcta 100500 agcacttttt attatttctc atttaatgcc cacaacaacc ctatgaggta ggtgttaatg 100560 ttattttttt tcacacgtaa gaaaccaaag catagagagt taagttgtac agaaggtcac 100620 aaagttagca ggtggtagag ccgtgatttg aacaaaggca atctgtttct agagtctaca 100680 ctctaatcta ctctttagac ctcctcataa tgtgatcatg cctaagtatt atttctccct 100740 gctaaacttt tgaaagaagc tggataataa tctattcaag tatgataatt ttaaatgtgt 100800 tttagcttag attatgatga aaaagaatat gaatgtacat tggatagcca atgagcatga 100860 atttacattg gttagtttct ctatttaaac cttcagaagg cttaaagtct cacctgccct 100920 ggacagtagg gccaatccac cttcatatag aggtatgcct cagttagctt gcaaacaagg 100980 ctatattttc ttcaaaacgc tctttgaatc tggccaagta gcctgaatta gtactctgtt 101040 gagaatcaag ttttcacata atacagcatg gcaaacatgt ttttgcaaat agtgtaacta 101100 aggatcaaaa agtaaaatta cttgcccatg cctcaaatat gggacctctt actctaattt 101160 caatgttctt cctgctggtc aagattatta gatgaaaatt ataaatggac atcagttaat 101220 attaaattat tcatcactta gaacaaggat gaatgtatta tattcgctct taccttttat 101280 ggcctccaga gattcttaaa gaatgtgaaa tttgaaagaa aagataaaaa agtcatgatt 101340 cttctaatct cacactttga aaaggtgata tggaaaggat tctaatccct tgataaattg 101400 tgatttcaaa aacaaaagtt gctcaactta aaaaaaaaaa cactggttat tttcctttgt 101460 aagagtaaaa acaaaaatat gtaaaaactt ttccaagaat tatgtaaaat tgattttaat 101520 gtttcttgtt ttactgtaat tattatacag caattgaaaa gtaactttta gctaagtttg 101580 tcatgttgct tcctgaagtg tccaaaccac gaactataga tggtcaccga cttatcatgg 101640 tttgacttta cagtggtgca aaagaaataa gcactcagta aaaattgtac tttgagtacc 101700 cttacaaccc ttctgttttt cactttcagt acagtattca gtaaattaca tgagatagta 101760 accaccttat tgtaaaatag gctttgtttt agatgatttt gtccaactat aagttaacat 101820 aagtgttctg agcatattta agttaggcta ggctaaagct gggatgttta gtaggttaga 101880 tgtattaaat gcatttttga cttagggtat tttcaacttt tgatgggttt gttgggatgt 101940 ttaaaactca ccacagttaa gtgccttttt attcttagtt gggatgagaa ccagagcaac 102000 tcaaccatta gtctcctcaa gccattttct ctttcttctt tcattttatt ccgtctttac 102060 tgcttggggt tttgattttc tgggaactgt atgcctaatg gacttattaa gtacctacca 102120 tagaataatg gatttcctta gtttccaagt atcccaattc ctgaacggtg ggttattaaa 102180 tctgaaactt gaaggaggaa atggaaattt aaagcaatga tcatcattta atcactttac 102240 aaagcacttt gctttaatct gttctctctt accacctcat caatgtggtc tcttaaaggc 102300 tatactgatt tcagttccta atgtgacctc acccccttat ttgttttatt taattttatg 102360 ggttttgttc tgtgttgttt tgtatttgtt ctagctaaaa aatagaacta attgcctatt 102420 ttttgataaa aggatcttgg atacttaaac tcattaaact aggcattaaa taatggatgg 102480 gcttttgctt aggatcacct aatatgtaaa gtacttcaca ccattgtcca atgatagttt 102540 ttgtaattta attaataaaa tcattagaaa taccgaatta ccactactct tattgctaat 102600 aactaagttt tggtcaaaaa gaaacaacag aataggaata tatactctac agagatctag 102660 caaacttgca tcaaaacagt attgagatac aaggctaatt cactcctgag aggaaattat 102720 tgttgttatt gtcttttgaa attaaaggaa tttatttata caatatgaag tatcacattt 102780 acatcattta agcatcaata caagttttgt gacaaaatta ctatttgttt tgtgacatat 102840 taatgcaatt ttaagtccat gggtggttat atgttgcaca tacagaaata aagtctgttt 102900 tcatactgat ttggttgtta caaaaatgca tatgaaggtc taaggaaatt ctggcttaca 102960 gtttagtgaa accaaaacct ctaattttca gaaagcttca atatagttga gaagtatgta 103020 gagttgaatt tgaaaattca ctttacaaaa atatccttag gaatatgttg aacgaactga 103080 ccaccaccaa caccttcaca cacagaccaa tttgaactgt cattgtaatt gatgttaaga 103140 agtgtgtgtt tgtgtaaatg cttgaattgc gaagtagatg aattaacttg ataaacatgt 103200 caattaagtg tcatatttat tggtttcaga agttaattgt gaatgattag cctactttaa 103260 aaaacctagt ggaaataaga aagagtaaat tctagttctg attatgacat ttattcaatt 103320 tatttaacta ggatttatca aggactgact tcaggcattt taatgggcac tgatactagt 103380 tattatgttg agcaggtcac taactgttac tcctcatctg caaaacaatg gttaaaaatc 103440 tctttactta cttgtgagat tgtttcacaa ataaaatttg aaatgaatga agatcctttg 103500 agagtacatg tgctagacaa ggaattatta atggaactat taatagatcc agtttctgac 103560 caggtaccgt ggctcacacc tgaaattcca gctcttttgg aggcctagat aggaggatca 103620 cttgaggcca ggagttcaag accagtctgg gcaacataga ctccatctct acaaaaataa 103680 aaaattagct gggcatgttg gcacgtgcct gtcgtactag ctattcagga agctggggtg 103740 ggaggatctg cttgagccca ggagtcaagg ctacagtgag ctgtgattat gccactacac 103800 ttatcctgag tagcaaagca agactctgtc tcaaaaaaaa aaaaaaaatc cagtttcctc 103860 ttgctatttt actcaagaac ttactaagaa tattttacca gttataaatt aaaatgccaa 103920 ccattaatta gaaggaattt tttaatatat taagcactgt caaattcagg gagttgatta 103980 tggtgtaaca aacagaaaac ctaaattgaa aagttcggct ctttcctgta ctagctgact 104040 aaacttgtgc aaatcattta acctattgag gtttatttaa tcatttgtaa ctgaaatata 104100 cttatttcaa aagaatagct tatgaagaat aaatgtaata cgtagtcatt ttataaatta 104160 taaatcacta taaaaatata aaatgttaac agtatcagta aacttaaaat atatgtttaa 104220 gtgactgagc aattaacaca ctttgttaac atttaaattg ttaaaacaag ctgacagtct 104280 taatgcctga gcatgttata tttattttta aattataaat tcccaataga tgtgctacac 104340 aaaagatgga gcatagtatc ttcaccagaa agggagatca ccttagtgaa cctgaaaaaa 104400 gatgcaaagt atggcttggg taagtcaccg tgagattctt gaaggtctat gattgttggg 104460 gattcagagg aaaagtctat agcatagcat tggcattgca gtgccagctc acttctggtc 104520 tcaagatact gactggctgc ccacctacaa gcccatcaac ctacccgccc agtcaccaaa 104580 tgcctaataa gaaatgccta caagaaatac ttccacaaaa tttaatatgt gttacctact 104640 aatcatttga tatcaatagt ccccacattt ctgtgtttca ggcaggctaa tcattagtct 104700 ttgaaagcag caatatgaaa atctttttaa aatgtgttat tttacaggat ttcaaattat 104760 tggtggggag aagatgggaa gactggacct aggcatattt atcagttcag ttgcccctgg 104820 aggaccagct gacttggatg gatgcttgaa gccaggtact ttacattttg gtagttttct 104880 aagtattttc tgacaggcat gaatttagga acttaggcca aactaaaata attgagaaag 104940 agatgatatt tctaagattc agaataaatg tatctttgtt gttgaaaata ctggattgtc 105000 tatttgtaca ggagaccgtt tgatatctgt gaatagtgtg agtctggagg gagtcagcca 105060 ccatgctgca attgaaattt tgcaaaatgc acctgaagat gtgacacttg ttatctctca 105120 gccaaaagaa aagatatcca aaggtaatgt gaatgtctct tacttatgta ttctgtttca 105180 cttttctgtc tcattccttt ttagtgatat tcgcacaaaa atggattcat tgtgtacaaa 105240 attgatgcaa cttaagtaaa ctgtgattac ttaatgtgtt ccatctttct tttgtcaaat 105300 cagagataga gtcatttatc attgtgtagt taatattaca taatagttat atataaagtc 105360 ctgtcctgaa ccagatgatg aaaaggaaag gaccaccacc aaaaaccaga aattttaaaa 105420 caaaaccata tcattttgtc tcattatccc agtcttcagt ggctgagaga caaagcactt 105480 gatgaagatc agatgacctg cgtttgagct ttgcctgtgc cttttattag ctatatgact 105540 taagccttct tgagccatag ttttcttttg tttttactta aagagtagac agtgatcttt 105600 gccctgcttt gtctgccttg cacagagtta tttgttacga ggatcaagtg gtaggacagt 105660 atttgtggaa gaagcacaat aggcccctgt ggcgtagaac agtgcagtgg gaaacaggga 105720 gggttgcaga atccagggtc agattctgtt tctaccacct aaaactgtac acattgagca 105780 aaatcacatg aaccttctaa gcctcactgt gctcgtatat caaatggtga ctataaacat 105840 gcttatctta tagattatga aaattaaatg agataataca tgtaaagaat gagcacattg 105900 cctggtacat atgaagcatt taaatgtgaa ttttagctgt cattaatatt gtttttcaaa 105960 aacattgaag tgctagatac aagtaagtta ccttcatgcc aaagatattg ggaaatacat 106020 aaaagaatta gtaaaaaaaa ttagctgaaa aacaatttta gacatagctt tggattctta 106080 tgataaaata gaagatgaaa aacatgaaca tgttatatgt tgtgataaaa tcttattaaa 106140 ttttatatag atgagtcatt ttgagtatga tttcttctta ctggatatta tatatatttt 106200 gtatgtctgt atatgtacac atataaataa tatgttacac acttgtttac tgtgagcaaa 106260 cacaatcgat agaagggaaa tagaaaacac caccactgcc cacaggaact ttatataatc 106320 taattataat ctagtcacat taggcaaagg aagacaacta cagttggaaa tgttgtaaca 106380 tacttctaag tttaaagcag ccaagactag aaattttaca ttgggtccca ttattcacca 106440 ttttttaacc atttctgaat cataggaatg cagaataaat ttattgcccc ctgaataaag 106500 ctctaaggga tttccatctt actcatgttt tcagtagatg ttttgtagaa aatttattca 106560 tttgtccaac aaatatttat tcagtgcctg tgatgtgcaa gacaaaaaac tctgccctaa 106620 tggaagttac tctttatcag gggaggcaag tattcttgtc tgactagaca gatttttaat 106680 tgtaactatg gtaagtgtta acaagaggcc caaggtgcca agagggaata taacagagga 106740 actttaccta ttgtgaggat cagaggagcc ttttcttctc agcagagttt tgtgtggttt 106800 ttttttctgt ccatgctaaa taaaaattaa aagcataatg ttaaaagtat acacctgtga 106860 aattgtttct tcagaaagta ggtgaatctt atcatggtat gtaactattc tgtagtgtca 106920 ctttgaaaag aggtaaaacc caaaagaact tagaaaatta ccaatgtgta ttctagctac 106980 ccctgttaat tgttaagcac caaagaggaa ggcttttagt tttgtttttg tttgctaatt 107040 tttaaagtta cagaatacat actagtttat taaaaataaa tccaatttat gcaaaaccta 107100 tgaaataaga agttgaagtc cccttacccc atttcctagg gaaacttttt ggcatacatg 107160 tagccttctg tgtagaatag atatatatgt gatgtgtgtg tgtgtgtaaa tatatatata 107220 tatatatata tatatatata aacacaacac atacacacac tattttttaa aaatctgttt 107280 tatactctaa ataccattct gtaactgctt actcaacata ttctgttgct atccatgtac 107340 atgcatatct ttttaatgca acattatatt tatgttatag acatatcaaa acttacttaa 107400 cttttcttct attgttatgt atccaggtta gctataattc tattataaat gttactccaa 107460 caaatacacc ttttaataca ccattgaaaa tgtatgtatt tctagaggtt agatgcctgg 107520 aactagatta aagagtatgt acattaaaat tttgacaagt gccaccaaat tggacttcaa 107580 aaagttttac caatttatag actaaccaag tagatatagc agtgcttttc tcctcatacc 107640 atcagtggtg cttaaaatta tcagtcattc tcatttttgt cagccaaata agtagagaac 107700 tgcattaaac tgcaggtccc tgagcaatag tgagaatgtc ttttcatata tttactattt 107760 gtattttact ctgaatttcc agtctacata tcccttgttc cgtgggagtt ttgaaaacct 107820 cttttttgtt gaattttagc aactctttgt atattaggga tactaattct ttgtttattg 107880 tttgttgtca caaatatttt ctctccagtt gctcattact cttaattttt cccttgttgt 107940 caattactac ataaaacttt taatttcata taaattctca tctttaattc ctttacacgt 108000 gtctttggtg gtttgtgtct tcagaaagct ttttcaagtg gcgttttgtt tgtttgttct 108060 ttgagacagt cttgccctgt cacccaggct gaagtgcagt agcacaatca ctgctcactg 108120 caggctccgc ctcccaggtt caagtgattc ttctgcctca gcctcccgag cagctgggac 108180 tccaggtgca caccatcacg cccagctaat ttttgtattt ttggtacaga cagggtttca 108240 ccatgttggg caggctggtc tcgaactcct ggcctcaagt gatctgcctg cctcaacctc 108300 ccaaagtgcc gggattacag gattacaggc atgagccact gcgcttggcc taaagtggct 108360 tttgataaga actatatata agcaatttgg agttgccttc catgataatc acttggagtc 108420 caaaaagtgc aatctagtag gtcaatataa agtaagtgtg caaataacta tttaataagg 108480 acaaagaatg tgggacacta agaaagtata aattatctgt ggaatcagta gagtctccac 108540 agagaagcct ggtttgaaat ggatcttgga gaatggaaat ggggagttaa ggtgaaaggg 108600 gtatgcattt caatagaggt tgtcacaaga atgaccaaag gagaaagcaa agaaagtcta 108660 ccaaacacat gacctaatgg tgttttgtgt gtcatcctta taaaatcctt ccaacaatct 108720 tcaagaaaca ttgtgtatgt gtgtaagcac gtgtatcact aacttgttac tctcattgat 108780 ggattttgac ttttagtgcc ttctactcct gtgcatctca ccaatgagat gaaaaactac 108840 atgaagaaat cttcctacat gcaagacagt gctatagatt cttcttccaa ggatcaccac 108900 tggtcacgtg gtaccctgag gcacatctcg gagaactcct ttgggccatc tgggggcctg 108960 cgggaaggaa gcctgagttc tcaagattcc aggactgaga gtgccagctt gtctcaaagc 109020 caggtcaatg gtttctttgc cagccattta ggtgaccaaa cctggcagga atcacagcat 109080 ggcagccctt ccccatctgt aatatccaaa gccaccgaga aagagacttt cactgatagt 109140 aaccaaagca aaactaaaaa gccaggcatt tctgatgtaa ctgattactc agaccgtgga 109200 gattcagaca tggatgaagc cacttactcc agcagtcagg atcatcaaac accaaaacag 109260 gcatagttta attttaatat tttggttttc tcatttaaca aagcaaaata gcagcaaata 109320 agttacagag cacaataatc tacaagatgc tttcattatt ctggaaaaaa gaaatagttt 109380 atatcttcta attgctactg catttgatgc taactttcag agaaatcaac agctttggat 109440 aataacttta aatggctatg actttgcaaa cttgctatct aataacccaa agaaggaata 109500 tgcagattat gattgttttc ttaccagttg tttgtctctg gcatatttaa tgtttgtatt 109560 aataagagaa ttttaatatc tgaaaattgt ttctaaatag ttcgtataat gggcatttga 109620 attcactatt tatagtctaa attcttctga agttctgaat gaatgatgat aacgacattg 109680 aaaatagctc attctggctg ggcacagtga cccacatcta taatcccaac actttgggaa 109740 gcagaggtgg gaggattgct tgaggccagg agttcaagat cagcctgggc aacataggga 109800 gaccctatct ctacaaaaca tttcttaaaa aattatccag gcaaggtggc atgtatctgt 109860 agtcctagct ccttgggagg ctgggtggga ggatcgctta agcccagaag cccaggcgat 109920 cgagccagac cctaacagaa agaagggaag gaaaggagga agggagggag agagataagg 109980 aagggaagaa agagagtagc ttattcctag aaatgataca aatttaaact caaattcaca 110040 agcagtttta gaaaaaaatc taacgccttt tgtttactga aaaatcaaca ttccttataa 110100 gagttatact cttataaata gggcttagct gttgttccca tgtttatatt attggattta 110160 taaatataag taatgtaaac atgaaatccc attttagagg cttgggttaa aagctactgc 110220 ttgatatata ttgattatta aaggaaataa aactaatttg taaatttagg aatataaaaa 110280 gcattggacc aggattatat aaaagccagg tttgaactgg gttctatata ggtttccatc 110340 tgccatatct agcagtttga cctgaagcaa gctctttaat ctctggatat cagtttcctc 110400 aaccataaaa tatgaataca ttggactaga tgatctctaa gatctcttcc aacctttatg 110460 ttctttgact atactctatc ctttaatatc ttgctttttc ataatttttc caaaaacaca 110520 tatttgtctt tcagtaataa ttcattttga ttctagccag ctttgtcctg ggctaggttt 110580 aaaaaaaaag aaattaaaaa aagaaaaatt ataattcatt ttgactctaa caagaaatct 110640 ttgtttgttt ttctttgtta aggaatcttc ctcttcagtg aatacatcca acaagatgaa 110700 ttttaaaact ttttcttcat cacctcctaa gcctggagat atctttgagg ttgaactggc 110760 taaaaatgat aacagcttgg ggataagtgt cacggtactg tttgacaagg ttttcaaatg 110820 ttttctcttc tttaatttcc agcagcctat tgtatgtcaa ctttttaatt gaattatttt 110880 gcatcaaaag ggacacatca aatacctcca aaattctaaa actgaatcat atctaaaaac 110940 tattttaaaa attgtgttag tcactttttc ctgtgatttt aaaaaaatta gacaaacact 111000 acctttttct ccatagattt aatacttgct ttatctgaat ataaaacttg caaattgtaa 111060 aattaatgta atgctttgta gatatttgac agtttctacg tgagcataga ttatatatct 111120 ctaacctaca ttattagtaa ttaaagactg tatatttctg tatactctcc ataatatgta 111180 ataccttgta aacatgttag tatcttaaaa ttagaagttc ccaaggaata tatgtatctt 111240 taaggtagtc agaatgtgag cataggctat ttgataaaat tatttttgaa ttatactgat 111300 gaatataata tccctcatta gtatactaat gaatatactg tacatcagca catgctgatg 111360 ggatgtcact gctttggcta atgaatcctt tctaggcctg agatttgaaa gagagtgcaa 111420 aatttttcat gttataaaat attattttgt ctttttctct ttagggaggt gtgaatacga 111480 gtgtcagaca tggtggcatt tatgtgaaag ctgttattcc ccagggagca gcagagtctg 111540 atggtagaat tcacaaaggt atagtgttta tattatgtgg gaattatatg tatgaatatt 111600 acaacaaata gataagaaat tataaagttg ataactgacc ttcaaattca tgatatgaaa 111660 taagaacata ctcaattata aaactgtagc attaagaaac tctttgatgc catttcaaaa 111720 actcttcttt ccagcttatt ttctagtatc agaagatatc tatacatcaa cattgtgtga 111780 gaagttaaaa aaattaaaaa ggaaagaaaa tatctagaca gtgctttcat tcatatttta 111840 catgtactat gaagcaaatt gctgtaaaaa cactgtcatc tacacttgtt ttttttgttg 111900 ttgttttttt ttttcgagac agagtctcac tctgtcaccc aggctggagt gcagtggtgc 111960 gatctcagtt cactgcaacc tccgcctcct gggttcaaat gattcttgtg cctcagcctc 112020 ccaagtagct gggactacag gcgcccacca ccatgccggg ctaatttttg tatttttagt 112080 agagacaggt tttcaccatg ttggccaggc tggtctcgaa ctcctgacct caggtgatcc 112140 ccccactttg gcctcccaaa gtgttgggat tacaggcgtg agcctctgag cccagcctga 112200 tatctacact tttagtaagg actaactagg aactttcctc caatctctat atatttatag 112260 ttcaacttat cttctctctt gatttaaatt tatttttata aagatactgt tctaaaatat 112320 acttaacatt agacataaga ttggggaata aattaaataa catattaaag aaactctgta 112380 acacaatttc ttccagaatt tgcctgagtc cctcctcaaa caaatgaata cgaaataaga 112440 ccataagatt taaaagaaca tgtaggattt ttatttatga tttgaactgc ctaattttta 112500 ggtgatcgcg tcctagctgt caatggagtt agtctagaag gagccaccca taagcaagct 112560 gtggaaacac tgagaaatac aggacaggta acagatcatt ataccaacct tttacagtac 112620 cttagaagag caaaacaatg tgtgaataac atcagttctc attgagatct ctaaatttgt 112680 cagctaatca agaaaccaag cctgatatat ataaccatct gggttgttga tttttccttc 112740 caaattgaaa tgcaagtatt acaagacatt ttttactgag gaagctgact ttctatgtca 112800 catttaacgc ttacattacc aaagagatct gatgggggag ggatggaaat tgcattttaa 112860 atttgttgta taaacatctc atttctagtg gttttcactc ttattcttta gccttaacac 112920 aaaatttatt ttgttgaagt acattttgag ttagggagtt taaccaaatt atctataatg 112980 gtctttggag gtttttgttg ttgttttgag acagggtgtt gctgtgaggc ccaggctgga 113040 gtgcagtggc gcaatcacgg ctcactgcaa ccttgacttc ccaggctcag gtgatccccc 113100 tgcctcagtc tcccaagtag ctgggactac aggcttgtgc caccatgcct ggctagttta 113160 ttttttattt cttgtagaga ttgggggcgg ggggtctccc tatgttgccc atgctggtct 113220 cgaactccta gacaagaagt gatcttcttg ccccagccta ccaaagtgct gggactacag 113280 tgggactaca ggcgtgagcc accacacctg gctttttttt ttttttttaa ttgagatgga 113340 atttcgctct tgtcacccag gctggagtgc aatggcatga cctcggctca ttgcaacctc 113400 cgcctcccag agtcaagcaa ttctcctgcc tcggcctgtc aagtagctgg gattacaggt 113460 gcccaccacg acacctggct aatttttata tttttagtag agatggggtt tcaccatgtt 113520 ggccaggctg gtctccaact tctgacctca ggtgatctgc ccaccttggc ctcccaaagt 113580 gttaggatta ccagcatgag ccactccacc tggccattat catacatttc taacatgtat 113640 tatatttata atagattctt tttaatcatt tatctttcta tacagaaatg taataaaaac 113700 ttgattttgg aactttcaac cccttgcttt tgttcctcta tttttttttt ctcccccttc 113760 atttggtgga ccaaatttgg tagttacttt aaatgatttt ataccattaa ctatacaaag 113820 tcctgaaaat gtatctattt tcttagcatt cttcttaatt aatgaaatgc tattttactt 113880 atccaggtgg ttcatctgtt attagaaaag ggacaatctc caacatctaa agaacatgtc 113940 ccggtaaccc cacagtgtac cctttcagat cagaatgccc aaggtcaagg cccagaaaaa 114000 gtgaagaaaa caactcaggt caaagactac agctttgtca ctgaaggtca ggccttggga 114060 gactacaatc tcacctttaa attattcctc gcctattcaa aatttgattt ttacatgttg 114120 gattacagtt aatgccctag ttttgttcat tattcttgtc aagtacaaat aataatctga 114180 catcacacca tactgaataa agacagaaac atatttgcag ctcatagggt ctgaaagact 114240 ttggataata aagtcatgca tgattatggt cttttaaaaa tgctttaaat tgttgtaaaa 114300 ttcaaaatag aatttggtaa gtgaaaaaat aaagaaaaac aaatgctgag atgccttcaa 114360 acccatggga aaccttgacc cttagatttt tgtatttcta tttaatttaa ttttaagaac 114420 tgtgaatcaa actctgggca gatattcaca tagtagtgcc cagaaagtgg tctttgttac 114480 aaactatgct agcctttgga cagatcacta attggtagta agaaaattaa gaatgacagt 114540 ggctttccag taccctttaa gattctgtct tcttaagagg tttatatttc ctttacttta 114600 taaatgatgg tgatggtgta cagtcattgt tttattttac acaaacgtta gcaactctga 114660 atcagtcccc aaaataatga gaaaaaataa cacagactat attatttttt cctgaatatg 114720 aaaataaaat taatgtactc attttatcat actgctcttt attctttatt tcttccatct 114780 tttttttttt ttttttttga aacagagtct cgttctgttg cccaggctgg agtacagtgg 114840 cgcaatcttg gctcactgca acctccgccc ctgggttcaa gctattctcc tgcctcagct 114900 tcctgagtag ctgagattat aggcacacac tgccacatgc ggctaatttt tgtattttta 114960 gtacagacgg ggtttcacca tgttggccaa actggtcttg aactcctgac ctcaggtgat 115020 ccgccctcct cagcctccca aaatgctggg attacaggtg tgagccacca cacccagccc 115080 catcattctt tctttaaata gatttttttt ttaaacaccc aagccaacca tgagcaaaga 115140 ctttaaatgt attttttaat tattttctgg ttattgttct tttaatttat ttagctgata 115200 agaaatttat tgaaatattg caatttatct gagttaaatt acacctcccc agaacattac 115260 aatttcaatt tatttccaca taacctcctc taacatttat tttgttcttc ttttcatctt 115320 tctcacgctg tatacctgag tttctcccat acctgtcctt ctgtggagtt tccccttttt 115380 ttgtctgtta tcgtactctg ttttgttttg tttttgtaga gattggatct cactgtattg 115440 cccaggctgg tctcaaactc ctgggttcaa gcaaccctcc tacttcggcc tcccaaagta 115500 ctggggttta taggcatgag ccactgtgcc tgaccatagt gtcttttaaa acacacaagt 115560 ttgatgcata attccatttt cagaatccta ctttcagaac tctccttcct aatcaaacag 115620 cttagttcat gcagttagtt gataagattt cttaatgatg gaaatagact gtaagataca 115680 gcttcagtat accattggag tgcagtaagt acatacagag ctataaatac gggaaaatgg 115740 gcttttaaaa tgtgtctaga agtatatatg tttgtatgtt cctatgtaaa cacagcatgt 115800 taataatatc taaatttttt ttatatcttt ttctccagaa aatacatttg aggtaaaatt 115860 atttaaaaat agctcaggtc taggattcag tttttctcga gaagataatc ttataccgga 115920 gcaaattaat gccagcatag taagggttaa aaagctcttt cctggacagc cagcagcaga 115980 aagtggaaaa attgatgtag gagatgttat cttgaaagtg aatggagcct ctttgaaagg 116040 actatctcag caggtgagcc cctagcatgt ggagtatagc atttttaatg atgagatgga 116100 ttggcctttc agaatggttt cataatgctg gtttaactgt accttcattt gtcattcatg 116160 gtacccccag gaagtcatat ctgctctcag gggaactgct ccagaagtat tcttgcttct 116220 ctgcagacct ccacctggtg tgctaccgga aattgatact gcgcttttgg tgagacttat 116280 gaaaagtaat ttacagtttt atagaatatc aacttagcaa ctaactaatt cagctgtggt 116340 ggtttcatca tgaattgttc tcctgggttt catacctagc tacttgtttt aggtaggcat 116400 gttatcttgt atgtgacaac ttctttgaat gtattccata tttatataat aatacaaagt 116460 aatttattca atttatttaa ctaggattta tcaagtactg acttcaggca ttttaatggg 116520 cactgatact agttattatg ttgagcaggt cacaaactgt tattcctcat ctgcaaaaca 116580 atggttaaaa atctctttaa taggaaaata acatttctgt aagatgcatt ataaatagca 116640 ttttaaagga ctacattgat ttgaggcacc agataggaaa aagtgaatga aactctcttg 116700 atgagcgtat aagttggtat cagtttttag aaaacaattt ggaaatactt aattaggcta 116760 ttaaaaatgg cctatattct gacagtatag aaaattacaa agtaatagaa actcaggtaa 116820 aaatttacat acaaagaagt tcttctagat ttctattaat aatgaaaagg tagaaacaac 116880 tctgtccaat aaaaggagaa ggcagaaata aaggtatagc catccattgg accattatac 116940 aggtattaaa attgttttaa agcatattta aggacttaag aaaatattta tggtagaacc 117000 ctaatttttg agagtatgag acaaaatata taatactact gtagttctaa cttaaggtat 117060 aaattgtaca atattaactg ttattttata tattattttc tctattgaac ataaattact 117120 tttatcatca gaaaattcaa tgcatacttt agtagaaagt tgttcaatgg tttattttca 117180 aataaatgct tctaaaattc atagaatggt cacaaatctc tttaaatgtg tccattacag 117240 accccacttc agtctccagc acaagtactt ccaaacagca gtaaagactc ttctcagcca 117300 tcatgtgtgg agcaaagcac cagctcagat gaaaatgaaa tgtcagacaa aagcaaaaaa 117360 cagtgcaagt ccccatccag aagagacagt tacagtgaca gcagtgggag tggagaagat 117420 gacttagtga cagctccagc aaacatatca aattcgacct ggagttcagc tttgcatcag 117480 actctaagca acatggtatc acaggcacag agtcatcatg aagcacccaa gagtcaagaa 117540 gataccattt gtaccatgtt ttactatcct cagaaaattc ccaataaacc agagtttgag 117600 gacaggtatc atcaatataa tgtgaaccgc tcaaagcaac tggttgttgt tagtagcagt 117660 agcagcaaca tgcatttctc ttaagaatga aatgtatgta tctgtgacct tcacagtggt 117720 taggcagagg atgactctat tggatgtcta gctattgtga ctgatagttt tagttagcaa 117780 accaataagc tctctagtca gtcagcctga gtctttcttc cctcttgagc atatttacta 117840 gtaactgaga aagttatttg tatttcactg ttaatcatac tacttaaaca gaaacagaat 117900 agacttattt aggcagtaac acagtgggag actagggacc agaaatatag aggggagata 117960 agggcagaga gtttgcaaaa ggtaagacaa agaagatggg gaaaagaaga aatgattgaa 118020 aacatagaag catacaaaga gaaggactac atcaatacat tgcataatta ttcatacatt 118080 ttactctttg gttatgtctt tgtatctatc cacatccaac tttatttatt caagtttttt 118140 tcctttgtat tttatccaaa ataaccacag gagtcagact tttattcttc tttcttcttt 118200 tccttattat gttgaaacac acattaagct tctgataaca ttagcttcag ctttgaatta 118260 acaactagaa atcaaaagaa ttttatttaa cctatcttgc tgactttatg cagcttaaag 118320 agcttcatca aaatagaacc taggccggcg cgatggctca cgtctgtaat cccagcattt 118380 tgggaggcca aggcaggtag attgcctgag ctcaggagtt cgagaccagc ctgggcaaca 118440 tggcaaaatc ccatctctac taaaaataca aaaattagtt gggcatggtg gcacacactt 118500 gtaatcccag ctacttgggt ggctgcggca ggagaatcac ttgatcctgg gaggcagagg 118560 ctgcagtgag ccgagatttc accactgcac tccagcctgg gcaacagagt gagaccgtgt 118620 ctcaacaaca acaacaaaaa aaacctagac agagaataaa ttattgttaa ttttaacatt 118680 taacagatat ggagtaaatt catagtccag agtcatacaa aaagtaacta ggatctcaat 118740 caaaatcaga catgaatatt tgttaagtgt tttctgtttc tggcacaaac taaccatatt 118800 gacattgaaa tgtatttaaa aatagtctta cttctttgtc tctgtagtaa tccttcccct 118860 ctaccaccgg atatggctcc tgggcagagt tatcaacccc aatcagaatc tgcttcctct 118920 agttcgatgg ataagtatca tatacatcac atttctgaac caactagaca agaaaactgg 118980 acacctttga aaaatgactt ggaaaatcac cttgaagact ttgaactggt aagttgtttt 119040 ctctatattt aaaaaaaaat ccatattttt taaaagaagg tgtgttcata aagtttccct 119100 ttagggaaaa agctatcttt aaaatagctt catatgtgtg tctaataaat ggataacata 119160 tctggtatgt ttctgtgctg agaaattagg aaataaggca aaaagacctg agtataaatc 119220 ctgactctac cactgacttg ctacaatttg gcagactcct atggaccaat cacttaattc 119280 ttctgagtct tggtaacttt gactataaaa tggagcaagt aacctcacag ggttgtggtg 119340 aagattaaat gaaataacat atgtaaagca cgtagtatag tatctgctac agagtagacc 119400 cttagtaaat attatttttg tctgcttctc aaattctgat gagttaccta tttgattttt 119460 aaccaagttt gaatgtaatt ttttttttct cctccacact ttttttgtgt gctcagatgg 119520 aatcctttac attgtaataa tagtcctaga acttctaaac ctacaaataa gatttagaaa 119580 caaaatttcc aagtataata tcctttacat tgattgaaag ttagcctttt taaatactgc 119640 ttttattatc caagtaataa atgtttattg tagaaaaatt attaaggaga gaagaagatt 119700 aaagccacta taatctgatt accccaaaac tgttaacatt ttggagctaa atttccagtt 119760 accctttttt ttttgcctat aattgtgcat gtgtgtattg gagatgaggg gtgtgcagca 119820 tctacatctt cagtttcatt cttagcaata gagtaaaaat aatctttaat ttttcttaga 119880 aatctttcac ccttgtaaac aacctccgtg tctcatttga aatcttttaa aagtatattt 119940 tatttataca acaaaattaa taagattgtg ataatcaccg aaagacttca tatttttacc 120000 aaaaaaaaag ctttgttgtg gctctttgca tctgtttaga aatatatggc tctttgcatt 120060 tgtttagaaa tatatgaatt ttttttctga acctttcctc cagaaagtat tttttgatca 120120 tcaaagtata accactattg tgtccttatt tatcctaaaa atataagaaa gaaagcagga 120180 gtaaattctg tctctgctgt ctctagacaa acataatgtt gtgcttaaac ataactttta 120240 cgtgggatgc agtgggggga cagtctgtct agaatcagac agactgtcta gagtcagaca 120300 gacttgactt cttcacttgg acaagttaag taacctttta aggtttgact ttctcctctg 120360 ttaagggaaa tgatagtcat ctttctgttt gtctatagtg cagaatagac aacctaaaag 120420 tattactgct tttttccctt aggaagtaga actcctcatt accctaatta aatcagaaaa 120480 aggaagcctg ggttttacag taaccaaagg caatcagaga attggttgtt atgttcatga 120540 tgtcatacag gatccagcca aaagtgatgg aaggctaaaa cctggggacc ggctcataaa 120600 ggtgagacat ttaagaggaa tggattattt gtgtaaatgt agacaaagag caagccagaa 120660 aaagaagatt gaattattgt aatactgtat ttatctattc ggtttatgct ttctgtttcc 120720 accacttaaa agtaaaggcc ttcatatcgt taacagtttg ggaaattatt ttatatatat 120780 atatatatat attttttact atactttaag ttctagggta catgtgcaca acgtgcaggt 120840 ttgttacata tgtatacatg aaccgtgttg gtgtgctgca cccattaact tgtcatttac 120900 aaatttgaaa gtccctttaa tctcagtaag gcataaaaca agctatctta ggtctcaagg 120960 acagaaagtt taaattactt agaggatgaa tttcctagat tagcaaaata atgatgcatt 121020 tgttagggat ttaacattat tatttcattg taatggcttg atcgttgtgc ctatgatttc 121080 cataataaag gggattacca ataaattaga gatcactgtt gtgaatctct tactagctaa 121140 tatatattat aaattaggag gattattgta ttttcttggc aatttagctt ctcttttcta 121200 aaaattgtga tcttcacatg cccctttctt gtttttgtag gttaatgata cagatgttac 121260 taatatgact catacagatg cagttaatct gctccgggct gcatccaaaa cagtcagatt 121320 agttattgga cgagttctag aattacccag aataccaatg ttgcctcatt tgctaccgga 121380 cataacacta acgtgcaaca aagaggagtt gggtaatgaa aagtcaaact ttgtacaata 121440 tgattttctt ggttagctta agagtaagta cttttatgac tgagaaaaca aatattttct 121500 attatttcaa ggtttttcct tatgtggagg tcatgacagc ctttatcaag tggtatatat 121560 tagtgatatt aatccaaggt ccgtcgcagc cattgagggt aatctccagc tattagatgt 121620 catccattat gtgaacggag tcagcacaca aggaatgacc ttggaggaag ttaacagagc 121680 attagacatg tcacttcctt cattggtatt gaaagcaaca aggtactctg caattattta 121740 tgagttttga ttgtgcgtgt gtgtgcattt caggtcattg attatacttc attctctgaa 121800 aatatattac tgaattagta attcatagac taaattggca ggacttaata aatttaaaac 121860 agacttcttg ataggcgatt ttgagaacac taagtgaata atagaatggt taccacattt 121920 atcagttagg atgttttcac ttgcaagtaa tagaaaataa aactcaactt ttgtttaaca 121980 agaaagggaa tttattggga gtttttttgt tttgttttgt tttcttttct tttttagaca 122040 gtttcactct tgttgcccag gctggagtgc ggtggtgcaa tcttggctca ctgcaacctc 122100 cgcctcccag attcaagcag atctcctgcc tcagcctccc aggtagctgg gattacaggc 122160 acccgccacc acgccaggct aatttttgta tttttaatag agacggggtt tcaccatgtt 122220 ggccaggctg gtctcgaact cctgacctca ggtgatccac ccgccttggc ctcccaaagt 122280 gctgggatta caggcgtgag ccaccctacc tggcccgaaa tttattggtt tatattggac 122340 tttagaagtc ccagagatag ggtggtcatc aggtgaaatc tgatcagggc tctaccttaa 122400 tttatttgct atttttagtt atttcctcct ccctgttatc agttttcaaa agactacatc 122460 attttcatac ttcccacctg tataccacat cacatcacct agagcagtct tcaaacagaa 122520 atctcaccaa tcactactat ttaagcaagt actgtgtacc aattgcgtta tgcctaaatt 122580 aaggtcaatc tctaagttgg aagcaaggga taagaatata cagatgctcc tcatacagtg 122640 gggttacatc ccagtaaacc catggtaaat tgaaaatatc ataagtcaaa accacattta 122700 aaatacccaa cctaccaaac atcacagctt attagcctag cctagcctac cataaacagt 122760 tttacattac ttacattaca ttatcctaca gttggacaaa atcatctaac acaaagctta 122820 ttttataata aagtgttgaa tatctcatgt aatttattga atactgtaat ggaaatgaaa 122880 cacaggatga ttgtatgagt attcaaagta tggtttctac caaatgcatg tcacttttac 122940 agtgtcataa agctgcacca tcgtaagttg gggaccatca gtatcgattg gcttaagcca 123000 gtcctggctc attcccagag ctgggatagg attaatccca ctggaacttc atgcctgcta 123060 cccatgaggc atagaactac cgcatctact caaccttata acagtttcac attataaaac 123120 atgctaatag caacttttct ttcacttata atggaaacag attgagaaaa tgtattagtt 123180 tcctattgct attataaaaa attactataa gtttagtggc ttaaaacaac acaagtttat 123240 tatattaacg ttctgaaggt ctgaaataca aaatgggcct tactgtggta aaatcaaggt 123300 gtcagcaggg ctgcattcct tctgtaggtc ccaggagaaa atctattttc taccctctag 123360 agactcccca tacaccttgg tttatggctc acttccatct tcaaagctag gaactgcagc 123420 accctctgct tctgttgcca cgtctctttc tgtgactcag actttcctgc ctccctcttt 123480 cacttattag gacccctgtg attataatgg gcccacccag ataatccaaa ataacctccc 123540 cacatcaaaa tctgaaccta atcatatata cagtttcttt tgccatataa atagtaatat 123600 cttcagaggt tctgaggatt agaacagaat cattagaatg taaacatctt ggaaggggat 123660 tattctgcct accacaattt acaggaatcc aggctttcta gattacagac ttaagtcata 123720 taaaggaaaa attcacattt ttgtttgtga attatttctt ttaaagtatg ggaacttgtt 123780 gatcaaatca ttgatgataa gcttatttat tccttctgaa cctgtaaatt agattgtgta 123840 cttttttttc cccttgaaca tagtctttga cttgattcct tcatatatgt ctaaaaattg 123900 gattggcata caattgtttt catagatcta cttgaatgtt aattaggagg ggagggaagt 123960 cttcaaacaa cctggaaagt atttttgtga aaattaacat ttttgctaac tttaggtcca 124020 actgaatatt ttgcctcaaa attagtagag cactcttcag ctcagccttg aagtcatttt 124080 cttttgtctt tctgctttta tcttagctgt cgtcaccaaa aatacagtca tggtagtcac 124140 agttattttc tcctttgttc ttcttctagc tctctcttca ttgtgtttat ctaccctctt 124200 ttattaaagt ccatagggta gcaataatgg agtgatgtat acttgtggta attatctgta 124260 tgtccacctt ctagagactc ctcatactcc ttggtttatg acttccttcc ataaagggaa 124320 ctgtaaaggg tttaggattt tactgtactt gcaagctaat aagctagcct gtctttgtta 124380 catggatact ggcagaagac ataaaactcc tgaatcagag ataaaagact attactaatg 124440 catagcaagc agcatgagca tggcattagt gtcagttcca cgtcttccaa gtcccgtaaa 124500 aatgatgtat gtgacgcacc tccccccgcc cacccaggca aagcagtgcc tggtatcaca 124560 tcacacaaaa ggaacaaaag caaaacacac aaaccagctt caacttacac ttggttactc 124620 aaaagaacaa gagtcaatgg tacttgtcct agcgttttgg aagaggaaaa caggaaccca 124680 tcaaaccaac caatcaacca aacaaagaat aaattccaca atgaaagcac gtattttgtc 124740 tttttgcatt ttggtgtata agccatcaat attcagcaaa atgatttctt tctttaaaaa 124800 aaagtggagg aaagtagaaa tttaccaagg ttgttggccc ggggcgttaa atttacagat 124860 ttttttaacg agaaaaacac acaaaaaaag ctacctcagg tgttttttac ctcagcacct 124920 tgctcttgtg tttcccttag agattttgta aaactgatag ttggagcatt tttttttatt 124980 tttttaataa aaatgagttg gaaaaaaaaa agatatcaac tgccagcctg gagaaggtga 125040 tagtccaagt gtgcaacagc tgttctgaat tgtcttccgc tagccaagaa cctatatggc 125100 cttcttttgg acaaaccttg aaaatgtttc tttaaaaaaa aaaaaaaaaa gatgacaaag 125160 aaaaacagag ataatattgg agatgtcctg aattttaata gggtacatgc cattagggct 125220 ttttgcacta aaggatgaac atgtactggt ttatgtggac aagccattat accaccagac 125280 tgcaatgcca gtttcctcta cggtgaaacc ccgtctctac taaaaataca aaaaatctta 125340 gccgggcgtg gtggcgggcg cctgtagtcc cagctactcg ggaggctaag gcaggagaat 125400 ggcgtgaacc cgggaggtgg agcttgcagt gagccgagat agcgccactg cactccagcc 125460 tgggtgacag agcaagactc cgtctccaaa aaaaaaaaaa aaatgatgta tgtgggcctg 125520 tggatttgta cacatgcaat aggttgtatt ataggagagg aatgctatga gaagagcctt 125580 gggaacccac cattttgtag cagtctgtaa gaaagcctgt tttttgttgg gggagagaag 125640 ttaccacatc cttcatggtt gcacactgca gatacaacct taagaaacgg cccagataaa 125700 aagaggtcag gaccttgcat tttggggcta gtcagcaaga acatacaggg gtactcagaa 125760 ctttaagtat attgcctctc ccaatactgt acaccttagg caactcccct cttctctcaa 125820 ttatcagcaa caataagatt gcatactaat cttctatttc tgaggtgcta tctttttggc 125880 tgttttgtac tttgggtggt accattctta taatcctttg aatagaaata cttcatctag 125940 attttctctt taatttaaaa gaaaaacacg tatcaagggc tttagatata taaaacttaa 126000 tgaactgtga tttctaagtt atctttaaac tattgactaa gtgacagtga accgagttat 126060 tagataatga atattagcag tgttttaaat aaaaggggaa atagggtgat atgttaaact 126120 gaagcccaga gaaaacctac gtaaagaagt gattcttaat cttttttggg tcaagaatat 126180 ctcccgggcc agtcacggtg gctcacacct gtaatctcag cactttggga ggcctaggca 126240 ggtggattgc ttgaactcag gagttcgaga ccagcctggg caacatgaaa aaaccccatc 126300 tctacaaaaa atacaaaaaa atagctgggc atggtggcac atgcctgtgg tcccagctcc 126360 ttgggaggct gaggtgggag cattgcttga ggccaggagg attgcttggg cctgggaggt 126420 caaggctaca atgtccaaga caatttacag ttgtcttttt ttacaacaca gaaatgatct 126480 tccagtggtc cccagctcaa agaggtctgc tgtttcagct ccaaagtcaa ccaaaggcaa 126540 tggtaaggat atattcattt tactgtactc tcctacggta atgggaatgt aaaatggcac 126600 atccattttg gaaaacaggt tgacaatttc ttaaaaatta taacttacac ctaaaatata 126660 atccagcttt ttcactgcca gctgttcact tgaagaaagt aagcctatat tctacataaa 126720 aacttggaca gaaatgtttc tagcacttac ttgtagtagc caaaatttga aacaactcaa 126780 atgtccaaaa actgttgaac tgaaaaactg gttgtaatat atccaaacaa tgaaaagcta 126840 cacagcaata aaaaggaatg gactattgat acaagcaaaa aaataattaa aataaactca 126900 aaataaatgt tctgaattaa ataagccaga gcataagaga aatagttcat actgtatgat 126960 tctattacac agttgtagac aatgcaaatt atagtgacag cagctcagtg gttatgtggg 127020 acaaacggga aggaagcatt taggggaaca ggagaaagag attacaacta ttatgtttca 127080 tactctgcca atatgattgt tttgaaccgg tggtgtatta ttggtatact tttttatttt 127140 tcttagaaat ttaataatat ttttcttgca aggaatatta aaatccattc ttggactctt 127200 tgtaacatca tccacagaat tctaaagact tgtctataaa aattccatct caacttttat 127260 ctttctaggc agaattattt cagggtcatt cccaaataga ggttcttaaa tgtatttacc 127320 tatatttgtt tctttctttg ttttgttata aagttttcca aactctaccg tatttttctc 127380 agtctcttga aaatataatt taatgaatga agttatattt aaatatgtga tgttttagct 127440 gtaagtgaaa tataatctcc ttttttaata tattgaattt ttgtaatgat agctaagaat 127500 taaaattaac atttggttta aaaatacatt aaaagttctt ttctgtttta tccataattt 127560 attttcctgt gttgaattga tagtcttttt gaaatcagac tttaaaaagc ttactacctt 127620 cttttaaata gtaaagtgaa catagttaag cacctgtgat ggatcaccca ttcagtgcga 127680 aaaattataa tcagtgtatc acatgaacca ttcagcccaa actgagcttt gatgtgaact 127740 attttctttt aagaaattag ctttttcctc acacctgtaa tcccagcact ttgcgaggcc 127800 gaggcgggca gatcacgagg tcaggagatc aagaccatcc tggccaacat ggtgaaaccc 127860 cgtctctact aaaaatatga aaattagctg ggcatggtgg cacacacctg taatcccaga 127920 tacttgggag gctgaggcag gagaatcgct tgaaccaggg agtcagaggt tgcagtgagc 127980 cgagatcgca ccactgcact ccagcctggc aacagagcat gactctgtcg aaaaaaaaaa 128040 aaaagaaaaa gaaattagct ttttccttgg gataaaccca aaaatattag aggtttggaa 128100 tcaaatatta ttccatttat ttggttttta atcattttgt aatatgaatt atttttgtgt 128160 actaataaaa ataacaacat cccagaaatg tgagttttct ttaattattt tgatgtccct 128220 cttgtggttt ggattggctc atccccttac ttcctatatt gtcctttcag gttcctacag 128280 tgtggggtct tgcagccagc ctgccctcac tcctaatgat tcattctcca cggtaagaaa 128340 aagcccaccc tctttcatgt catacctcct tatctgagga actgcatgtt tgtgttttga 128400 accaaactga tttcatattt aaatatttgt cttctttaga tattcatatt aatagtaagg 128460 ctatatttta ctgaactaat aggccttgct aagtaaatca tacaacatag agcctcacat 128520 aggtaaccgt acatcattta gcacacactc agcttttaaa tacactaacc agttaaatag 128580 ataactttag tgcggagatt tttcttatta atgtgtaaaa ttcttttgat tgtctcttag 128640 accatgggaa gagaagaata atataattaa gagtggaatt gttcctttgg gctatttttg 128700 gcgagtagta accttcaagt tcaaatctgt gcaatcagtg aggaaaaaac agaagtagca 128760 aaaaaataaa taaataaaaa gtaggtttac ttgcttttga aagacttaga aaatgcttta 128820 ccaaatgatt aaatgagaga gctttaatca tttaagatta gcacagagaa atctaggggt 128880 gactaaacaa aactaataca tagttaaatt ccatttcatg ctctttttaa gtctactttt 128940 atgcccattt ggctaacatc cctttttgtg gttttcttcc tggtatgtaa tatacatttc 129000 tacagtgatc agagctagat cttcatttca tggaattgtt ttattccaca tgcatcccat 129060 acaatatgtt ctgaacttca atatggaatg gctttccatg taaaatacag cgctgaggga 129120 ttgctctttt attaatccga aagtcttatt atgtcaacat gagctggctt tagtgtggga 129180 ggagaaaaat aatttcatga ccagaattcc aaaattctac acctttcatt tcattatgtt 129240 gtctcacact tgtgatttgg tctagcaagc catgaaaaga taattacagc agaacatttt 129300 aaggtagtaa tgattgagac acaaaagcaa aaattttttg ttatttgtat gtgttgaaat 129360 tgagctacag caacactcac tattctctgt ttattcagaa tgtcttcaat ttcacatagc 129420 caaagcaact gaattttcat gtatttctag taatattcac actgtatagt gctcttcttt 129480 ttaagtaatc agtatgttgt tgaaagaaag aagagttgag tttttgtgaa attaacataa 129540 aaccctagaa accaggactt ttgctgttca tggctgccag cattttttgg ttggagttaa 129600 aatcttccag gaagtctccc aaacaatact gtgtccttga atgctaatat ctatactatt 129660 aatttctcat tgagaatgga gtttcataat ccagtgatgc tttttgatat tatattacca 129720 ctatttattt tttaaaattc tattgcatct accatgtgta ctttttatct taatagaatg 129780 agtgaaacct tgagagcaaa gcacaacctt ttatttgtat aaaattattt taatttattc 129840 caagcattta tttttgcatt tttttcaagt gatttttctt ttgataggct atgctccatg 129900 aagtgcttta cagttgaaca ttgcattcaa aatttacatt ctattcaata attattctat 129960 tgttatgaat tcattatttt tcttaaattt atatgagact tagactagat ttgaaaatct 130020 ttatacctaa tagattatca ggtcactaaa ttggagacta tatccatgta atacactcac 130080 aagtacttga aaagttggta ttttctcttt ccctcaactt ctaagcttta atagtcctat 130140 taaacttttt taaaattgta tgaaagacaa gtcttataaa attgcttcaa aaaagagatg 130200 tctacagtca gatattttaa gaagtactac ataatagagt tatcttttgg caactcaaag 130260 tttatattag caaggactgt gaaaattcct ggaataaaaa ttttgagtta atgttgtttc 130320 acctagtatt tccagatata tttaatgatg ggaagcccca tgccctatgc acatttaatt 130380 gcactgatat ttcctttcaa acactgatct aaggtggaga gatgtaaaat ggatcttgta 130440 ctaagaaaga agaggagaga gacaatgtgc agtcccccga tcctggaagt tagtaaaata 130500 ctatctgatg atttgctttg gttttatgct ttaggttgct ggggaagaaa taaatgaaat 130560 atcgtacccc aaaggaaaat gttctactta tcagataaag ggatcaccaa acttgactct 130620 gcccaaaggt agttttccaa atcagtcatc taattactct aaatgcccta ataattcagg 130680 taattaaaaa aaaataggta tcctcttttc tttgctttat atgttactgt agctttaaag 130740 ggaaagatta ttggtcaaat aaacaaaaga acaatatata aatgtcccag tattcattct 130800 cgtctctgag actaattttt tttaaatgat tgaaaagata gctgctgtgt tttacagtgt 130860 ttcttgtatt ttgtgaagta gcaattcaca ggctacctaa tagtttagaa aaagtatctt 130920 gaggatgttt tgtctgatct attatatcct taatcattgt aacataactt tgtttctttc 130980 ataaattaat acattgagag tcatttaaga aaataaacat taaattatta atgccttgtg 131040 aaaagccgta tcaccaacat tgattttagt ttattctttg taatttgcat ttgtgtggtc 131100 ttccatcata gcagccaggg tagttttaga actaaaaatg actggatcac attagtgtaa 131160 actacttttc cagtcattgc tacttttaaa attggttgct taaaatttga aagcacctag 131220 caaattctgt ttaacacctt gtccctttct cgtgtcaata tttttaaagt aaaaccccat 131280 gtaaattatt atttttcaag aatcttatat acaagaagat gacatttatg atgattccca 131340 agaagctgaa gttatccagt ctctgctgga tgttgtggat gaggaagccc agaatctttt 131400 aaacgaaaat aatgcagcag gatactcctg tggtccaggt acgtgaacca gatgaataaa 131460 ttggtatact atggagtaca aaaacgtctc tagggagcat tttttgagta aatatgtaat 131520 gcattagttc ttcttctgtt cctcattcat gtgtaatatt tcagaaacaa aacagaattt 131580 gttatctcct atttttttta ttttccatat ttgtaagtgg gttaccttat tagtgagatc 131640 tccaaatgta tcatttatat catggctttt acttctagta gggttagtcc aaacattttc 131700 ccccagccat tctcatttta attttagtag ataattttaa ccagaaattt tataccaaaa 131760 tgtacttgat catttcttcc taacttttct agttaaaaca ttgaaactat ttatggatat 131820 tggtttatac actgccttct tttgcaggca aatgaaaact tttctacttc ctcaatagtt 131880 ttataaattc ctcttggcct atatattcct ctctcaggta cattaaagat gaatgggaag 131940 ttatcagaag agagaacaga agatacagac tgcgatggtt cacctttacc tgagtatttt 132000 actgaggtaa caataatacc taaacaacct aggatatgac agcttgttac aattatgggt 132060 ttaacccaga aggtgaaata atcagagatt ctttcctgtt ttactcaaaa attaaattta 132120 ggaggaaaac ggagattaat ttcatgtgtt acattaaagt gtcatcctat cctagtgaaa 132180 gaatcattac acaaattttc tcaaattaaa aaaaatagaa aaaaaaacaa ttagttttca 132240 aaaatgtaat gctaaacttt ataaattatt ctttaaaacc ttaaaactta ggatcttctg 132300 ggatattagg ctaaggaaaa gcatgaaata gtagataaat tatatttcag gttcttcaag 132360 ctcagcatca ccctatgtat acaaatctga ccttgcttaa tattctggga taattctcct 132420 cattatcctt cttagtcttc ctacttcata tcttcaaaat tattaaaact gtgctggttt 132480 gaatgttctt acactagtta tcatgcatgc ttatacttac acacaatctc atccatacat 132540 gactgttcat taaatattta caaataatgt gtatatatac aaggaagctt acggctgata 132600 agtatgtatt tctcaagcta caagaataat catacaaata ttagatatct caaaatgtgg 132660 cattcgctag tggtttttct taagatgctc tttcatataa tcagaatatt aataattaca 132720 gtaaaaatag gctctttaga gaagattttc tgaacatttt aagtcatgac tttatcacat 132780 ttttattaat atttaatagt aatattaaaa tgccccttaa aatgtatgtt gtaatgtctt 132840 ttaactaaga aaataaaaat ctttaattgc catttcagaa atgtgatgta ggccgggcgc 132900 gttggctcat ggcggtaatc ccagcacttt tggaaggccg aggagggcag atcacttgag 132960 gtcaggagtt caagaccagc ctggccaaca tggtgaaacc ctgtctctgc caaaaatata 133020 aaaaattagc cagatgtggt ggcgcacacc tgtattccca gcccctcggg aggctgaggc 133080 aggagaatca cttgacccag gagacagagg ttgcattgag cggagatcat gccgttgcac 133140 tccagcctgg gcaatggagc gagactcagt ctcaaaaaaa aaaaagtcat gtcacatgct 133200 ttttctttta aaaaagtaag gaaagcttgt taatatagat tctcatttat actgagctat 133260 gactgtttta tggcagaaaa cttctttcaa gttatctttt ttttattatt ttcattatga 133320 aaatattaca tccttattgt aaaaaagttt ccaacagaat cttcaaaact gttaagtcct 133380 agccgggcat ggtggctcac gcctgtaatc ccagcactct gggaggccaa ggtaggcgga 133440 tcacctgagg ttgggagttc aagaccagcc tggccaacat ggagaaaccc cgtctctact 133500 aaaaatacaa aattagccgg gcaaggtggt acatgcctgt aatcccagct actcgggagg 133560 ctgaggcagg agaatccttt gaacctggca gacggaggtt gcggtgagcc gaaatcacgc 133620 cattgccctc cagcctgggc aacaagagcg agattctgtc tcaaaaaaaa aaaaaagtcc 133680 ctttttaaaa acatatttat cttattcatc tgaggtagct attgttaaaa attttgattt 133740 ctacctttcc actgtgcata tcaaaacata aatatttgta tacatacata attttttaat 133800 atacgtttta tcacatggtt ctgaatttgg ttttcactta acaatcatta ccctctttcc 133860 atgtgagacg tataaatttg cctcatactt tttaaagcct tcctatcatt ttattgtaag 133920 gttataccat aatttattaa attggccatc tgttaatgaa ttttagattt cttatcaata 133980 agaggaaaca aattattagg aactatataa ttgtcttgcc actggagtac agatagatcc 134040 tgcaaataca tgcattgaga atacattttg ggctagataa attagtgctt cctgaataaa 134100 tgggactttt gctttagaat ctgttttaaa taatggtaaa caaagcaaag aaaatgaggg 134160 aacaaattta ggaaaggagt aacagggatc ttagattaaa acatttaaaa attttatttg 134220 tatctaattc taggaacacg tttaaatcac tatggcaatt atattcataa gcagacaaat 134280 ttaaaatttg caaatatgac taatctcccc tagctgaaaa gaagaccaag ctggtattct 134340 ggaaaagttt tctgtttcat cttgtatttc tagaatatta cctacatttt agaactggct 134400 agttttaaaa attatttaga acttctgaca ataatctttt gtaagttctt gaaatcaccc 134460 taaacaaatt gtatattatt tactgaattg gttctaacag tatattctgt aactttgaaa 134520 gttttatcat gtggcaaaag ttaagatgct aaccattggt attacaaaag tataggaata 134580 tcttcttaca gaagaaagat tatacctctg atagctattt atacattcat tgtatttctt 134640 attcagtatt gtaattgtac tctttggtac ctcttagtga agtacttcag gtcaatgcct 134700 gtgtctcatt taagaatgaa agaatgaatg ctaatcgtat acattactat aaattattgt 134760 ctacagtttc aaaaccattc agctattgaa ctcatctgac taattttgct ggggataata 134820 gggtaagaag aggtgttagg gtttctgtcc taaatttgct tgtccagtct agtagtcagc 134880 ttgagggaag tacacatgta aataagtaaa taatttttaa aaagctatag aaacatattc 134940 tgttaaatgt ttatatggag ttcagtggga cctacaaaga aggggggaaa tggtaggggc 135000 tacacaggag taggtggata aagttattaa agctttctaa agaattagca tcttaaaggt 135060 atttgatagt taagctagga aagagcattc catacatacc gtggagctgc tttagcagag 135120 gaatgaaggc atagatgagc ctggaacatt caggacacta agtcattgcg agtagggtat 135180 cacagggtgt cttgaaagct aaacctaaaa agataggcaa ggtattagtt catgaagtga 135240 cttacatgcc atgccaagga atttgatctt tccacatctc ttgccactga aatggatcaa 135300 tatgctttct aattctggtt attttttaat ggctttaatt tcttcaaaca ttgtcttctt 135360 atgtagtgtt tttaatttct taagcaaaaa caaggcaaaa acttttagtg actctccatc 135420 acctgaggat aatcctgctt gactggttgg atcttaggac tggctttatg ggcattcaac 135480 cagtgcaatc acacagaacc ctgtgcttgt aagagcctcc tactcctaat atgctatagt 135540 gctgtgctat caccaacttg aagttcttag taagttttta acaagagata ccttatttgc 135600 atgtgactct tggcactaca aattaggtag ttcgtcctag atcaaggaga tgtctcctct 135660 actctcaagt tactggatct ggattccttg agcactagga ttgtaaaata accttcaaag 135720 gggctgacca cgataaaaaa aaatcttaaa tatattcagt gaggcagtac cacagctgcc 135780 tcctcttcca aaggtccttc agtccatagt gacaagaaac tgaaggccaa tcttcttaac 135840 gcaaccctcc cccatacaca agtgaacttt acaaaaatag tggtaattgg ttaatacagg 135900 tatcactgta gctttttttt ttttttttga gtaacagcaa gatttattgt gaagggcaaa 135960 agaacaaagc ttccacacac agtgtggaag gggacccaag caggttgccc cactgtaact 136020 tatttctaat tgagctttac ctcaccattt tcatttaata attgtgttat taaaattttc 136080 atatttataa tagcacttaa ctcttataaa aggctttgta ctttctaaaa tcattataca 136140 catactatat tcttagacca ggattgtaat ggggaataag aaatccaaat gactttagtt 136200 ggaaaaaaat tttaatccag actaaaatga gcagcttctc gaaagagatg agtttccttt 136260 tagttgacag tggattaaaa ccttttttct tctactgtag aacttctaca tttacatcaa 136320 ctaaattgaa attattatca gggtaattta attatggtac tttttaactc tacaaagtct 136380 gtaactgaaa ggtcatatta caggtgtcat ttttattaaa tggatgaaat aacctatgtc 136440 acagacataa gtgtgtgtgg gcacacagtg gtgaacagat cgacatgatt cctgccttgg 136500 tagagcttaa tgatggagag gaaaggagaa aaaatcaaac acacaaatag atatgtaatt 136560 acaagttgtg ttaaggtctg tgaagtttgt ttgttgtttt taagtgccac acacacacac 136620 acacaaaaag aataaccaag gaaacctgct ttagattggg tggatagaaa acatcttcag 136680 gaggagaaga cacaatgctg aattttttag taaggattca cccttagaag ggctttgtgg 136740 taggaagaga tgagtgattt tgaagaactg aaagacccat gaatttgaag ccactgggta 136800 aaggggagat tataaaagta gacaggggcc agataattca gggccttcaa gggaatttcc 136860 tatttgttaa gaaaatttgt cctgataaag attcaattgt ataatttacc gaccatttaa 136920 gaatacaatt tgggggtggt cacttccaaa atgaccgaat aggaacagct ccagtctgcc 136980 actcccaacg aaatcgacgc agaagacagg tgatttctgc atttccaact gaggtgcctg 137040 gttcatctca atgggactcg ttggacagtg ggtgcagcct acagagggtg ggctgaagca 137100 gggtggggcg tcgcctcaca cgggaagcac aaggtgtcag gggatttccc tttcctagcc 137160 aagcaaagcc atgacagact gtacctggag aaatggtata cccctgacca aacactgtgc 137220 ttttcccaca gtcccagcaa ccagcagacc aggagatact gtcccatgtc tggctcagcg 137280 ggtcccaagc ccacggagcc ttgctcactg ccagcgcagc agtctgagat caacctgtga 137340 cactgcagct tgaccagtgg ggggcatcca ccattgctga ggcttgagta gctcacagtg 137400 taaacaaagc ggccgggaag cttgaacagg gcagagccca ccgcaactca gcaaggccta 137460 ctgcctctct agattccacc tctgggggca gggcagagca gaacaaaagg aagcagacag 137520 cttctccaga cttaaatgtc cctgtctgac aactctgaag agagcaatgg ttctcccagc 137580 atggcgttcg aactctgaga atggacagac tgcctcctca agtgggtccc tgatccccgt 137640 gtagcctgac tgggagacat ctcccaggag gggccgacag acacctcaaa caggcgggtg 137700 ccctctggga tgaagcttcc agaggaagca tcaggcagca atatttgctg ttctgcagcc 137760 tccgctggtg atacccaggc aaacagggtc tggagtggac ctccagcaaa ctccaacaga 137820 cctgcagctg aggggcctgt tagaagggaa actaacaaac agaannnnnn nnnnnnnnnn 137880 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 137940 nnnnnnnnnn nnnnnnnnnn nnnnattctg cattccaaat taagtggctg gtttatctcc 138000 atggatctcg tggaccagtg ggtgcagcct ccagaggggg gcgtgaagca aggtggggcg 138060 tcgcctcaca cgggaagcac aaggtgtcag gggatttccc tttcctagcc aagcaaagcc 138120 atgacagact gtacctggag aaatggtata cccctgacca aacactgtgc ttttcccaca 138180 gtcccagcaa ccagcagacc aggagatact gtcccatgtc tggctcagcg ggtcccaagc 138240 ccacggagcc ttgctcactg ccagcgcagc agtctgagat caacctgtga cactgcagct 138300 tgaccagtgg ggggcatcca ccattgctga ggcttgagta gctcacagtg taaacaaagc 138360 ggccgggaag cttgaacagg gcagagccca ccgcaactca gcaaggccta ctgcctctct 138420 agattccacc tctgggggca gggcagagca gaacaaaagg aagcagacag cttctccaga 138480 cttaaatgtc cctgtctgac aactctgaag agagcaatgg ttctcccagc atggcgttcg 138540 aactctgaga atggacagac tgcctcctca agtgggtccc tgatccccgt gtagcctgac 138600 tgggagacat ctcccaggag gggccgacag acacctcaaa caggcgggtg cccctctggg 138660 atgaagcttc cagaggaagc atcaggcagc aatatttgct gttctgcagc ctccgctggt 138720 gatacccagg caaacagggt ctggagtgga cctccagcaa actccaacag acctgcagct 138780 gaggggcctg ttagaaggga aactaacaaa cagaaaggaa tagcatcaac atcaacaaaa 138840 aggacatcca caccaaaacc ctatctgtag gtcaccaaca tctaagacca aaggtagata 138900 aaaccacaaa gatggggaga aaccagagca gaaaagcaga aaattccaaa aaccagagtg 138960 cctcttctcc tccaaaggat cgcagctcct tgccagcaag ggaacaaaac tggacagagg 139020 atgagtttga caagttgaca gaaatagact tcagaaggtc ggtaataaca aactttccca 139080 ggcaaaagga gcatgttcta acaagtcgca agaaagctaa aaaccttgaa aaaaaggtta 139140 gatgaatggc taactagaat aaacagtgta gagaagacct taaatgacct gatgaagctg 139200 aaaaccacag cacgagaact tcatgacaca tgcacaagct tcaatcgccg attcgatcaa 139260 gtagaagaaa ggatatcagt gattgaagat caaattaatg aaataaagca agaagacaag 139320 attagagaaa aaagagtgaa aagaaatgaa caaatgctct tagaaatatg ggactgtgtg 139380 aaaagaccaa atctacattt gattggtgta ccggaaagga caggcagaat ggaaccaagt 139440 tagaaaacac tcttcaggat attatccagg agaacttcac taacctagca aggcaggcca 139500 acattcaaat tcaggaaata cagagaacac cacaaagata ctccttgaaa agagcaaccc 139560 caagacacat aattgtcaga ttcaccaagg gtgcaatgaa ggaaaaaatg ttaagtgtgc 139620 agccagagag aaaggtcagg ttgcccacaa agggaagccc atcagaataa cagcgatctc 139680 tcagcagaaa gcctacaagc cagaagagag tggaggccaa tattcaacat tcttaaagga 139740 aagaatgttc aactcagaat ctcatatcca gccaaactaa gcttcataag tgaaggagaa 139800 ataaaatcct ttgcagacaa gcaaatgcta acagattttg tcaccaccag gcctgcctaa 139860 caagaactcc tgaaggaagc actaaacatg gaaaggaaca tccagtacca gccactgcaa 139920 aaacatacca agtggtaaag actatcgatg ctgtgaagaa actgcatcaa ttaacaggca 139980 aaataacgag ctaacatcat aatgacaaga tcaaattcac acataacaat attaaccgta 140040 agtgtgtatg ggctaaatgc cccaattaaa agacacagac tggcaattgg ataaagagtc 140100 aagacccatt ggtgtgctgt attcaggaga cccatctcat gtgcaatgac gtgcataggc 140160 tcaaaataaa gggatggggg aagatctacc aagccaatgg aaagcaaaaa aagcaggggt 140220 tgcaatccta gtctctgata aaacagactt taaaccaaca aagatcaaaa aagacaaggc 140280 cactatataa tggtaaaggt atcaaatcaa caggaagaac taactatcct aaatatatgt 140340 gcacccaata caggagcacc cagattcata aagcaaatct ttagagacct acaaagagac 140400 ttggactcct acacaataat aatgggagac tttaacaccc cactgtcaat attagacagg 140460 tcaacaagac agaaggttaa cagggatatc caggacttga attcacctct gtaccaagtg 140520 gacgtaatag atatttacag aactctccac cccaaatcag cagaatatac attcttctca 140580 gcaccacatc acacttattc taaaattgac cacataattg gaagtaaaac actactcagc 140640 aaatgtaaaa gaacagaaat tataacaaac tgtctctcag accacagtgc aatcaaatta 140700 gaactcagga ttaataaact tactcaaaac cacacaacta catggaaact gaacaacctg 140760 ctcctgaatg actactgggt atataacaaa atgaaggcag aaataaagat gtcctttgaa 140820 accaatgaga acaaagacac aacataccag aatctctggg acacatttaa agcagtgtgt 140880 agagggaaat ttatagcact aaatccccac aagagaaaga aggaaagatc ttgacagcct 140940 aacatcacaa ttaaaagaac tagagaagca agagcaaaca cattcaaaag ctagcagaag 141000 gcaaaaaata actaagatca gagcagaact gaaggagata gagacacaaa aaaccattca 141060 aaaaatcagt gaatccagga gctagttttt tgaaaatatc aacaaaatag actgctagca 141120 aaaagtcaaa ttgtctctgt ttgcagatga catgattgta tatttagaaa accccatcgt 141180 ctcagtccaa aatctcctta agctgataag caacttcagc aaactctcag ggtacaaaat 141240 caatgtgcaa aaatcgcaag cattcatata caccaacagt agacagagcc aaatcatgtg 141300 tgaactccca ttcacaatta ccacaaagaa aataaaatac ctaggaatcc aacttacgag 141360 ggatgtgaag gacctcttca agcagaacta caaaccactg ctcaacgaaa taaaagagga 141420 cacaaacaaa tggaagaaca ttccatgctc atggatagga agaatcaata tcgtgaaaat 141480 ggccatactg cccaaagtaa tttatagatt caatgctatc cccatcaagc taccactgac 141540 tttcttccca gaataggaaa aaactacttt aaagttcata tggaacccaa aaagagtcca 141600 catagccaag acaatcctaa gcaaaaagaa caaagctgga ggcatcacac tacctgactt 141660 caaactatac tacaaggcta cagtaaccaa aacagcatgg tactggtacc aaaacagata 141720 taaagaccaa tggaacagaa cagaggcctt agaaataata ctacccatct acagccatct 141780 gatctttgac aaccctgaca aaaacaagca atggggaaag gattccctat ttaataaata 141840 gtgctgggaa aactggctgg ccatatgtag aaagctgaaa ctggatccct tgcttatgcc 141900 gtatacaaaa attaactcaa gatggattaa agacgtaaat gtaagaccta acaccataaa 141960 aaccgtagaa gaaaacctag gtggtactat tcaggacata ggcatgggca aagacttcat 142020 gactaaaaca acaaaagcaa tggcaacaaa agccaaaatt gacaaatggg atctaattaa 142080 agagcttctg ctcagcaaaa gaaactcatt aagagtgaac aggcaaccta ccaaatggga 142140 gaaaactttt gcaatctacc catctgacaa aggactaata tcctgaatct acaaataact 142200 taaacaaatt tacaagaaaa aagcaattcc atcaaaaagt gggcaaagga tatgaacaga 142260 ctcttctcaa aagaagacat ttatgcagcc aacagacata tgaaaaaatg ctcatcatca 142320 ctggtcatca gagaaatgca aatcaaaacc acaatgagat accatctcat gccggttaga 142380 atggcaatcg ttaaaaagtc aggaaacaac agatgctgga gaggatgtgg agaaatagga 142440 acgcttttac actgttggtg ggagtgtaaa gtagttcaac ctttgtgaaa gacagtgtgg 142500 caattcctca aggatctaga actagaaata ccatttgacc cagtgatcac attactgggc 142560 atctacccaa aggattataa atcacgctac cataaagaca catgcacacg tatgtttatt 142620 gcagcactgt tcacaatagc aaagacatga aaccaaccca aatgtccatc gatgatagac 142680 tgaataaaga aaatgtggca catatacacc atggaatact atgcagccat aaaacaggat 142740 gagttcatgt cctttgcaca gacatggatg aagctggaaa ccatcattct aagcaaacta 142800 tcacaaggac agaaaaccaa acaccacatg ttctcactca taggtgggag ttgaacaatg 142860 agaacacatg gacacagggc ggggaatgtc acacaccagg gccttttggg gtttgggggc 142920 ctgggggagg gatagcatta ggagaaatac ctaatgtaaa tgatgagttg atgggtacag 142980 caaaccaaca aggcacatgt ctacctacat aacaaacctg catgttgtgc acatgtaccc 143040 tagaacttaa agtataatag aaaaaataat acaatttggc atttctttct aattgtagca 143100 aactgctcct gctgcagtat ttgaatctct gaaacacacc atactcagtt aaagtatgag 143160 ttgactaatc tttaatgata aaggggcaat atattataat ctaacatatt tgaaactact 143220 aagattttct tgaagctttt tttagatttt aaaattgaag tagaaaagca cataccaaat 143280 gtgcatatct aaataatcat taattcacac tttcatcttt ttcatctttg tctctttcct 143340 attaatattt ttaatataag aaatgaaggc caggctggct tcagtggctc acacctgtaa 143400 tcccaacact ttgggaggct gaggcaggag agtagctcaa ggctaggagt ttaagaccag 143460 cctgggcaac atagtgagat cccatctcta cagaaaaaaa aaaattttta attacctggg 143520 catggtgaca tgcacctgta gtccctagct actcaggagg ctgaggcagg aggattgctt 143580 gagcccaaga gtttgaggtt acatgagtca tgattgtacc actggactct agcccaggca 143640 acagactcca tctctttaaa aaaatgaaaa gccaagatga gtgtgaagtt acctaagtgg 143700 gagcagcaaa gactgttggg ccactgatgc ctcagccact gtttggagtg tattaattga 143760 atgtcatatg tgtctttgta atataaggat gaacaataac agtaaatata ggaaataact 143820 aacaggaaaa aaatagtatg cgattttttt tgttacaatg ggctgatttg attcttatat 143880 atttttattg taggccacca aaatgaatgg ctgtgaagaa tattgtgaag aaaaagtaaa 143940 aagtgaaagg tgagaaaata attttcaaag tatccataat gcttctgtct atctataaat 144000 gctctgaaga tttccatttg ttttccagta taaaataagc atagttgagt agattataaa 144060 actatggttg aatattaaga atttttaaaa ttttcgggcc aggtgcggtg gctcatgcct 144120 gtaatcccag tgctttggga ggctggggcg ggcagatcac ttgaggtcag gagttcaaga 144180 ctagcctggc caacatggtg aaaccctgtt ttctactaaa aatacaagaa cccaggcatg 144240 gtgtctcatg cctgtaatcc cagcactttg ggtggctgag atgggcagat cacttgaggc 144300 caggagttgg agaccagcct ggccaacatg gtgaaaccct gcctctacta aaaatataaa 144360 aattagctgg gtgtggtgac acatgcctgt aatcccagct actcaggagg ctgaggcagg 144420 agaattgctg gaacccagga ggtggatgtt acagtgagcc gagatcgcgc cactgtactc 144480 cagcctgagc aacagagcaa gactctgtct caaaaaaaaa aagaaagaaa aaaagtttta 144540 aattttttgt tacaaggagg ttctagtgac atgtgaaaat gtgtttatta tactattgct 144600 tcaagaaagc aatattctct taactattgg aaaaaatgaa tgaaagcgtg accctaaatg 144660 gaaatgtggc aacaatcatg atagtgactg tcttcaccta ttgggttatg ggtcatttat 144720 ttttcagttt ctctattttt ctatacttca aaatttttta atttttaatg agaaaatgaa 144780 accaaaaaaa gtaagaaacc cacaaaatat gttttaaaac ccataaaaat atttttaaac 144840 aatttctaat tataaagtaa ggtctttttt tacaaaaata tatatgaggg aaagggtttt 144900 tatctatgag gggacttcaa aaagttcatg aaaaaataga gttaaaagat aaaaatataa 144960 aatataaact ttattaacat aagctccatc aagtttagca cacttttgta ggtgatgata 145020 ccagccattt agttaatccc caaaaaactg aaggtcctgc aaatttaacc atatcaatgc 145080 agtctttttt acattaactg aagaaaaatg catgcccttt acagattttt tgagattgag 145140 aaacaaaaag tcagaaggag ccaaataagg actctaagat ggattcctgg taatttccca 145200 ctgaagctca caaaattgcc ttgtttgatg agacgaatga gcaggaacat agtcacacaa 145260 gaggagaact ctccagtgaa gctttcccag acatttcatg gatgtagagc tttttaaccc 145320 agcaaaatta gtgttgtcac ccacagtgag ttagaacagg gggaaacatc tgtcataaaa 145380 gcagcgtaat tgctgccctg ttgacatttt gggagcatta gtccatgtcc tggtgtatac 145440 taatgtcatc agatgaaagt actctgcttt gttccccctg aatatcagaa agttaaaaac 145500 gtattcaggc ttttacgtaa tcctttttca cttcacctta gcactaaaca ccgttctcct 145560 acctagtttc tctttcctag ccatccacct taccaaagag ggcatctgtt atgcactccc 145620 aaaatattga gaacttgtac tgggtttcat tacattaagt gagtgcccag gtacaggagt 145680 gtccttctgg cctcctgttg tagcaaaagg ctatacccat caatagagac ttctttaaat 145740 aaattaagat acattcatat tttgcagtag tgggcagatg ctgaaaagaa ggagaaagag 145800 ctatatgccg gtacaattgt aatcactcat ccatgttgaa ggatagaaat aaaaccacca 145860 ccttctccat cctcaaatgg actccttcag tttaaagttc aaaaacggga tctgtccaag 145920 gataaatttt aaaactgtat taaaccattc tacatctcag ttgtttacat ctaccaataa 145980 attttaagaa ttgtggcttt ggttttctta gacattctat tttaaaatac tataataatt 146040 gtagagaaaa tcattcaggg ccatgtttaa tttgagtaca aaaatgaaga aaatgtttca 146100 aatatgtttt gttttcatag cttaattcag aagccacaag aaaagaagac tgatgatgat 146160 gaaataacat ggggaaatga tgagttgcca atagagagaa caaaccatga agattctgat 146220 aaaggcaaga attttaatga cagttttttc ctcaaaaata atgaattgga aaaatgtttt 146280 taagtgattt tcagactata tggatatgct gttttaccat atgtatacat tatttgcttt 146340 tttttttttt tttctttttt tgagacagag gctgggagtc cagtggggcg atctcggctc 146400 actacaacca ccacctcccc agttcactac aaccaccacc tccgcagttc aagcaatttt 146460 tcctgcctca gcctcgagta gctgggatta caggcgggtg ccaccatgcc cagctaattt 146520 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 146580 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn tatagataca cacacataaa 146640 tacatagaga tttatagggt ttacatatag aatatacaca cacacatata taaatatata 146700 aaataaataa aataaaataa agaccttcct agccaggtgc agtggctcac gtctgttatc 146760 ccagcacttg gggaagccaa gacaggagga tcacttgagg ccaggagttc aagaccagcc 146820 tgggcaacat agggagaccc cgtctcttca aaaatattta aaaattaacc aggcacagag 146880 ggtgcatgac tgtggtccca gctacttggg aaactgaggc aggaagatcc cttgagcctg 146940 gtagatcaag gccgcagtga gctgtgatta cagaactgca ctccatcgta ggcgacagaa 147000 caagattcta tctctaaata aataaataga ctttcccttt tgtaagatga ggtgaacata 147060 ggctgaaatt agttcactta gttaaattgg ttctggagga actgttttta aattgctgtc 147120 ttcctattag atcattcctt tctgacaaac gatgagctcg ctgtactccc tgtcgtcaaa 147180 gtgcttccct ctggtaaata cacgggtgcc aacttaaaat cagtcattcg agtcctgcgg 147240 ggtttgctag atcaaggaat tccttctaag gagctggagg taagtggctt ctgccaatga 147300 ttctctccca aagtgtatgc atttagtttg taaggaaaat gtatctttac tggcccaaga 147360 ttagaagaat ttttgaaaat tttccaactc taaaagcacc accttatcat atctagcaga 147420 aaattaattt ttctgattag gatcccaata atagtgattt aaaggaatca ctttaactac 147480 ttggaacttg atacatttcc ctgaagatta tccttcctgc ctcatagtta aggtaaaaat 147540 gtttaaaaaa aaaaaaaaag ccaagtataa atttcaacca tgcactaaac tttataatta 147600 gtgtattgta gacgtgtttc atcattaaca gaaggttcta atttaataca gctccaagaa 147660 tgtgtgtcct agttcaaagc agcaatggct cagagcccta gctcctgtgg tctcatggta 147720 ctgtccatat ttaccactag aaaagagagt ggttttgaag ttgaccttgc ccctcttcct 147780 caaaccatct gcttatttgc ctacttccta agctttgtag ccactaaaag gagttaactt 147840 taataagagg ttctgctttg tgcttgttgc tttgtatata ttcctcaaaa tattaattct 147900 gttatagatt gtgaaactga ggctcacagt aattaaggta tactcttctc atcgccatgc 147960 tatggaatga tttgttcttc aagttcttag atttaaatgt caccatcaga aaagttccat 148020 cacaaccctt acaaagtagt gtttataagg atttctttac cacagcagct tattgatttc 148080 ttcaaggcat atactacaat atttgtttac ttctttattg tgtctttctc ccaataagct 148140 gtaaaggcca ggagagccaa aatcttatct tcttgctcac cactgtattc ccatcactta 148200 ttacagtacc ttgcatataa tgagcatgca atatatattt tttgaatgag cgaatgaatg 148260 aaaagtgagc aagagttgac tttagaacct aggactatct gaccacaaca ccactaccac 148320 atggaatatt ctataaccct tacagactat actgtcaata aattgtgctc tagctcatca 148380 ctttatggca gagttgggtt tttttaattg tatttttttc taaaatataa acacttttaa 148440 acagaagtta aaaattaaga cacaaagttc tgtctcataa agttgactac aacgtgttca 148500 attaaaagat acttgtaaca atatatttca atgctgactt aacaaatcac tactgacttt 148560 agacttattt aggacatctg tatttaacac tcagaatcag ccttaatcaa ccaattttgc 148620 ccctacacat ttaaagtatt tgaagttatt actgaattac tgcttatctc aacaaattta 148680 tttccatgtt ttgcttacag aatcttcaag aattaaaacc tttggatcag tgtctaattg 148740 ggcaaactaa ggaaaacaga aggaagaaca gatataaaaa tatacttccc tgtaagttcc 148800 agtttggctt cagatttaat atgtgatcag tataatatta atggattaaa attttttgtg 148860 tttaacttac ctatccctca cataaccgtg tgcatgtgca tacattcaca gatttatatc 148920 agtaacaaat acattgaaat attccgtgta aatccccttt taaattatgt aggtattctg 148980 aaaatcagtt agaggaacct gaaatatttg ataggatatt cctgaatttt tactagtata 149040 cagtattaga aattagtcgg tgatgccaaa tcattaattt taaaatcttt ttaaaaatag 149100 gaactggctt ctggatgagg attttcttgg ttggattcat ttatcacaac caccatcaat 149160 ttattccact tatttttagt ttagagaaat atctatggta atgaatagct gtatatatat 149220 gcatatgact acagtggtac taccagccta cattagacat ttcagatacc agaagggaac 149280 aaaagcaatc attttggccc ggtgcagtgg ctcacacctt taatccctgc actttgggag 149340 gccgagggag gcagatcact tgagatcaga agtttaagac tagcctggcc aacatggtga 149400 aaccccatct ctactgaaaa atacagaaat tagccgagag tggtggctca tgcttataat 149460 cccagctact tgggaggctg aggcaggagg atcgcttgaa cccgggaggc agaggttgca 149520 gcgagccaag atcatgccac tgcactccag cctgggcaac agagtgagac tccatctcaa 149580 aaaaaaaata ggaaaaaaaa aagaaaagca gtaattttta catgtataaa aatcacatgt 149640 aaaaaaatca cactgtgatt ttttttaatt atgtatgaat gtgtgtgcca aaatactgac 149700 ctctagcaaa ttcttataat taccagccac atgtatatat gttagcactt tggattataa 149760 catatgacac actgacccta tctttaccaa gaaaccataa atctaaagat aaataataaa 149820 aaaaatcaat agtgacaagt cacatgataa gtaataatgc aattgtattt ttctaatcca 149880 gatagaaagt acaaattcat tttggaaagc ttcctgtaag aaatgaatct tagacaacat 149940 ttaaaaaatg gatcagatca ctgtttggca taaagtatat gggagttatt ttagacagca 150000 aaatggccag ttgaatatct caaaatcaga ataggacaag ccataaatcc aaaactaatg 150060 agtggattta ctcccacaaa acaaatgacc agtatggact aagagaaaga agtcaagtga 150120 gaagggcaat tggtagggga ttttgaaacc tatcattaaa aggttttagt ttggtaatca 150180 cagtaattac cagttaaatt tatagatatt tgaaatagaa atagaaataa cttctaaggt 150240 atgtaataca tataaattta ttctcttaga taaatcttag acaatataac ctcagtgaat 150300 gatagcttgt acatactttt cactggagca gcctggttta aaaaattaca ttttgactat 150360 atgaaattat aataaaacaa agataagggc ctttatgcct ggataataaa atgagctgtt 150420 attttcttta ttgtgttaat ttattgtttt ggctgcttat taaaagaata taattttatt 150480 aggtgagtga gagttaatta tgccaataac atttgcaata tatactttaa tagtgttatt 150540 gtaatactaa attgtgttct atgaaaaatt ttttggcatt gcctttcagt gctattatta 150600 ttatcatcat catcattaaa ataatgatgg agaagtacca gttgtttttc tttgtttctc 150660 tagttactta ttaggcaatt ctaaatgcat ttattaactt actaatttta atttcaacta 150720 aatctatgta aataatacca aatttcatat gtcagaaact cactaaacta acagcttaga 150780 tacttgtaac atgagcaaaa agaataaaca taaaataatt tggctgtgct acaatttgaa 150840 aatatacttc tattaaaata cgttggtgat ttcatctgtg actatgagaa tttctcatga 150900 tctttgactc atgcaatttg taagactctt gtttaaaatg catgatatgg atggctctgt 150960 tttgtggtgg aaaattcaca gatgatgcta caagagtgcc tcttggagat gaaggtggct 151020 atatcaatgc cagcttcatt aagataccag ttgggaaaga agagttcgtt tacattgcct 151080 gccaaggacc actgcctaca actgttggag acttctggca gatgatttgg gagcaaaaat 151140 ccacagtgat agccatgatg actcaagaag tagaaggaga aaaaatcaaa tgccagcgct 151200 attggcccaa catcctaggc aaaacaacaa tggtcagcaa cagacttcga ctggctcttg 151260 tgagaatgca gcagctgaag ggctttgtgg tgagggcaat gacccttgaa gatattcagg 151320 taagtgaatg aaatctttcc ctgttggaag gtgtatctcc tagttgtaat ccaagcctgg 151380 actctttccg tgattgcacc aatgttattt ctagataaaa gacagtgact tcctagttcc 151440 catgcaatgg aactaatgct agctattttt tctttatgta atataagttt aaatgtgact 151500 gtcttcatga attctgccag tttcctccag tatgtcctct actaaaatgg aaatgaaaat 151560 gcaggacttt taatgtgatt atcatccttg gtgatagcac aaaatggctc agaagttgca 151620 tgttggaaac ttgtgttttt atggtcagac ctctaagtag actcattgaa actactttta 151680 aaatctttaa gtagaaaata ttccctcata aaggcaactt aacatattta ggaatacatg 151740 gataatttta gcataaacag ttgttattca gatcattcat actgcagtta cctaaccact 151800 ggatcaatct agcttgaatt agataagtgg caatacctga agtaaagctg ctactgtttc 151860 ctcactctgt gttctccctc accttactac acgcctgtgc acagtatcct agctagatgt 151920 gagtaatgtt tcccatagaa atttagctat cttaaggaaa cagtgatttt acttttatag 151980 aaacaaagca tatcaattca gttctattgg tgtcatgtaa atgtagcctg agaatttctc 152040 tcataatttt tgattcatga ttttttattg atttacacta gcttacctat tacttaggct 152100 agcacagttg ttcaatattc ttccagtgat ttatccactt aatccacaca tttttataga 152160 actcaacccc tttatagaga tttggcagtc aacaacacag acaaaaaata tttctaacct 152220 catggagctt acattctgaa gaggaaatac cagtattgat agtgctgtgg aaaaaaatag 152280 agaaggacaa ttggctgggg gagaatgaga agtatgtcgt aattttcaac aaggagtcag 152340 ggaaggtatg agaaaatggc atttgaggaa aaatgtgaat gagttgagtg agccatggag 152400 ggaatatctg aggagaaaac cattccagtc agaaagagcc agtacaaaag tcctgagacc 152460 aaactgtgca cattgtattt aaagccacag agaatcattt ggcttgatga aagtggccat 152520 ggggaaagag aggaggaggt gaggtctaag aggaaacagg gccagattag gtagtgttgc 152580 agtgactctg acttttatct gaggtgcatt tggaatgggg tcaccagaaa aggttgttat 152640 caaaatgcaa tttgttttta gggtttccaa aaagtagttt ttatcgatat ttaaaatgtg 152700 gatctagcaa ccttgttgat agaggccttc catgtttttc ttaatagagc catttagttt 152760 cttccacttt tcctttgatc tgatcctata gacaagccaa aatttgaaag cacaatataa 152820 tattaagaat taattgtggc cgggcacagt ggctcacgcc tgtaatctca acactttggg 152880 aggccaaggt gagtggatca gttgaggtca ggagttcgag agcagcctga ccaacatggt 152940 gaaaccccat ctctactaaa aatacagaaa ttagctgggt gtggcaatgt gcgcctgtaa 153000 tcccagctac tatgaggcag gagaatcgct tgaacctggg aggcggaggc tgcagtgagc 153060 cgagattgca ccactgcact ccagcctgga caacagaacg agaccctatc tcaagaaaga 153120 aaaaaaagaa ttaactgtat gtgaacaata taacatgtca tgatccactt attctgttat 153180 acaatttcag accagagagg tgcgccatat ttctcatctg aatttcactg cctggccaga 153240 ccatgataca ccttctcaac cagatgatct gcttactttt atctcctaca tgagacacat 153300 ccacagatca ggcccaatca ttacgcactg cagtgctggc attggacgtt cagggaccct 153360 gatttgcata gatgtggttc tgggattaat cagtcaggat cttgatgtga gtacaagata 153420 ttggctgagt aagcatttgt tcagaaataa tgatggagtc taatttttga taatgtgttg 153480 tgatcttggg atattttaac ttatgagttt atatgactgc cttcattttc ttcttatatt 153540 attatagaaa attgtatttt tgtaaacatt ggtattcaaa actacataga ccgtgatcaa 153600 caaaaaataa tacttcaatt ttatacttgt tttactgggt gttttttaac tgtgtgctca 153660 gaggcctttt atgcagtatt tcattttacc ctttatagtc tttaggcttg tataagatag 153720 tattgttatc acactttaaa gatagaaata attgaagcac aaaggaaagt atttttttaa 153780 tgaaaaagct tgtatttttg tattatctat gggtaaaaaa tgtatatttt attataaaat 153840 taatgctaag tagtttctaa acaattactc tacataaaaa aattactata agagtataat 153900 cttacttttg aactcaaatt aatataaacc ttatttaaaa ttttagaata tcttaccata 153960 gataatgtgt aattaaaatc atagtgtctt aaaaagaatt ttagttaaaa gcactttaca 154020 cactagctgt agtaatttaa gtaggatgaa accaaatagt ctttttttcc ctcatttcca 154080 actgttcaat gtcagctgaa gtcaaaagat cttttttagg ttggaaacac ctttagcgga 154140 agagcagtgt gcaggaaaaa taatttacct ttttaaattg taatattaga aattagtcac 154200 acttcagggg gaagatgatt tcttttcttt gggggatttt caaatagatt aaccttccct 154260 aattcctaga aagataaaaa ataagaatac caagtgatga caaagtccat tcgccaagtc 154320 attttgtcca ggagagtttc ccaagactac cagaagggga agaagagtgg gatacagaat 154380 tttacataag cctcccctct gtgatccttt tgagattcaa atccagttat cctttgaatc 154440 taacacatat gtggtttcct ctgacagttt gacatctctg atttggtgcg ctgcatgaga 154500 ctacaaagac acggaatggt tcagacagag gtgagtcatg gctgggcctc ctaatgagaa 154560 tttttgtaaa gattctaata ttttttaagg ttcttattaa accatttttc ttttttgaga 154620 gttcccatgt tagagcataa aaccaaacat ttactgcagt gaggggcatt tttttttaaa 154680 tgaggactaa ttcagaaaaa aattaaaata cttccaagct ttttaaaatg ttgcctttta 154740 atttaaaaat gcaatatctg cactgaagag attacagaga atgggatagc atgctgggga 154800 cagagtttga gaatggtaca aaatactatg taattaatgg cattccttcc ctatttccaa 154860 cctgaaaaag agatagaagg taacattctt gctacagaaa ttccctgaga agtaatggat 154920 tcatcagcat tgactggaac acagcaaggc aggctggagt tgcttagctt caagaagaca 154980 ttctgtaagg agtgtgaata catgggtcca tttatcctct tttgatgatt ttcgtttctc 155040 ttacctgaaa ggaaaccatc acccactgac acaatggcgt ccttcacagg gagtgccgta 155100 tttagagtgt ctgtcttcac tgaagagttc cacaatcctc tttgtttata atggaagagt 155160 gggggatgta gaagccgttt tcaaatatcc ataaattaac atttctctac ctcttgaaaa 155220 atagggaaat ttgctatctt taaaaattag catttgccta ctttcctttc ataaaccttt 155280 ttaattcaac ttgtcttcta actattaagc tgatttataa tcacgctttt taggtaagga 155340 aaacattttg attgttataa gcagcacttt acacctagaa agttcattca ttcatttgtt 155400 cattcaacag atatttattg agtgcttact ttgtattagg aactcttcta ggccgggcgc 155460 ggtggctcac gcctgtaatc ccagcacttt gggaggccga ggcgggcgga tcacgaggtc 155520 aggagatcga gaccatcccg gctaaaacgg tgaaaccccg tctctactaa aaatacaaaa 155580 aattagccgg gcgtagtggc gggcgcctgt agtcccagct acttgggagg ctgaggcagg 155640 agaatggcgt gaacccggga ggcggagctt gcagtgagcc gagatcccgc cactgcactc 155700 cagcctgggc gacagagcga gactccgtct caaaaaaaaa aaaaaaaaaa aaaaaggaac 155760 tcttctaggt gcctggagca catcagtgaa taaaacaaag atccttgcta gaataacaaa 155820 gatattcttg caggatactg ataaggatgg aagaccatag acatgttaaa catgtaaatt 155880 atataggatc cctgaaagtg gtaagtgctt tagagaaaag aaaaatgaaa taggtaaagg 155940 gaatcagtca tggcagattg ggggtacgat tttaaacagg gcggcaccat tggcgaagta 156000 acacttaagc aaagatttga aggcaaagga gagggtcatg tagatctctg gggacaagag 156060 cctttcaggc agagggacca cctgtgtgga agtccaaggg tcttgagtgt tcaggtatgg 156120 tcacagccaa tgtggcgggc agggcacgag agaaggaaga gtgaaggagg aggtgaggtt 156180 agaggggagg tgacagggtc caggactttg gcttttctct gagtgaaatg ggagcctgga 156240 gtggcagtga tctgactcac attttaaagg actactaacc tgctgtgtta aaatgacacc 156300 aagtctgggg aggaaggtgt agtgttataa gcaaagagat caattaggtg acaagcaggg 156360 gtggctacag ctggagtggt aagtgtggac agagtgaaag aaacaggacg tgatgtgaag 156420 tagatttgct aatgggttgt atgtggtgtc agagaaagag tcaaggatga atgtgtggaa 156480 aagttaaaat acagataagc aaaaaagaaa cttaaaaggc cacttgtatt cctactgtca 156540 gagagctgtt aatgttttta ggagatgttc ttatattctt tgtcctaaac acatgtgcac 156600 actccttcat gctcacacat actatatata aaatagctca cacatgtagc tattttaaat 156660 gagattcaac tgtggttgtt gttttattac ttttcattta atatattgtg agttttttat 156720 ttgcagactc aattccttgc caaaaaaagt cagatctctg caccatcaac ttaatagaaa 156780 ataatttcac caaaggagtt cattttcaaa gaactttgat tttcatgctt ttgttccaaa 156840 atatttaaag acttattttt tggtttgttt gtttgtttgt tttttgagat ggagtctcac 156900 tctgtcaccc aggctggagc acagtccgtg atctctgctc actgcaacct ccacctccca 156960 ggttcaagtg attctcctgc ctcaccttcc tgagtagctg ggattacagg tgcctgccac 157020 ctcactttag tagagatggg atttcaccat gttggccagg ctggtcttga actcctggcc 157080 tcaagtgatc cacctgcctc ggcctctgag attacaggca tgaaccacca tgcctggcaa 157140 gacaattatt ttgaatagct tcttaagctg ttaatttttt gacattttaa aacatcaaaa 157200 tgagctcaac aaatccagaa gaaattatgt aggaaggtta tttttccact aagtataatc 157260 aaagcacaaa aaatattgta gtggcccacc aatcaaagac aacttcagtt agcactctag 157320 gatagttcca tcccgcatcc ctcaggcttt ttcttttctt gttttgccaa tctggtttct 157380 attataattt ttataatacc acacaattct ataccctgct tctttttttt tttttttttt 157440 ttttttttga gactgagtct cactctgtca ccaggctgga gtgcagtggc acaatctcgg 157500 ctcactgcaa cctccgcctc ctgtgtcaag cgattctcct gcctcagcct cccaagtagc 157560 tgggactaca ggcgcgtgcc acgacgccca gctaattttt gtatttttag tagagacaga 157620 gtttcaccat gttggccagg atggtctcga tctcttgacc tcgtgatcca cccgcctcag 157680 cctcctcaag tgctgggatt acaggtgtga gccaccgcgc ccagcctaca ccctgtttct 157740 tgcattcaac attctaacaa aatttttcca tattttcaaa actcatccaa catcacttcc 157800 aatagtggta tagctatata tatataatat ttacattata catctaaagt attctatctc 157860 actttttttg gccataggat caatatattt tctgctatca agtcatcctt tatgtcctga 157920 cacgtcttca agcagaagaa gagcaaaaac agcagcctca gcttctgaag tgacatgaaa 157980 agagcctctg gatgcatttc catttctctc cttaacctcc agcagactcc tgctctctat 158040 ccaaaataaa gatcacagag cagcaagttc atacaacatg catgttctcc tctatcttag 158100 aggggtattc ttcttgaaaa taaaaaatat tgaaatgctg tatttttaca gctactttaa 158160 cctatgataa ttatttacaa aattttaaca ctaaccaaac aatgcagatc ttagggatga 158220 ttaaaggcag catttgatga tagcagacat tgttacaagg acatggtgag tctattttta 158280 atgcaccaat cttgtttata gcaaaaatgt tttccaatat tttaataaag tagttatttt 158340 ataggggata cttgaaacca gtatttaagc tttaaatgac agtaatattg gcatagaaaa 158400 aagtagcaaa tgtttactgt atcaatttct aatgtttact atatagaatt tcctgtaata 158460 tatttatata ctttttcatg aaaatggagt tatcagttat ctgtttgtta ctgcatcatc 158520 tgtttgtaat cattatctca ctttgtaaat aaaaacacac cttaaaacat gaacaagcca 158580 aaactgtgtg cagacaaatt agacattttc agtgtgttat ttttcaacaa cacctaggcc 158640 cctgggaaga caaggacctc tagacaccac tttccatctc cctagttggc ctcagtcatg 158700 acagccatgg agagtagagg tgttgtcaga gatcctgata gatcttcact aaatactgat 158760 gtgggggtca tgtactggct taacagtagc tcagaaattc agtctttctt ccttctacct 158820 ctttgtgaat gttgcccact tattgagccc aatttatata taaatcagaa tattttcaag 158880 tcctagccac agtactcaac tgaccaaggg ctaatcaaag aaaacatatc aaactacctg 158940 gggggcgggg gtatatttgg ttctgcaaac aggaaggaaa agagattgac ttcaaagctg 159000 ctttagctta atggttctct gttctcagta ctaaattcat ttcactaaat tctaattcta 159060 acagtatttc tccattcagc cacgacactg taactggatg gatgttcttg accatgagtt 159120 gtccaggttc ttggcatgtt gaacaaagaa ttgaacaaaa tgctcagaca aagcagtgga 159180 agattaaagc atagatgttt tgaagtgaaa gtacactcca cagagtggaa gtgggcttga 159240 gcacatggct caagagccct gattataatg ttcctgggct tttattgaat tacaagagca 159300 tggtaacacc cctaagtacc ctttagaggc ctctgatagg ttacacccta cacaaatgaa 159360 gaattcagcc caggaccaat cagaggcagg attctgccca gaaccaatca gaggcatcct 159420 gcctgtgatg tataagcaaa tgaaagtttc agaatggacc aattacagac atacccattt 159480 gtgacatagg ggaggggagg ttcagagagg catgggcatt tggcccctca ttacttggtc 159540 ctggaaaggt ggggttttcc tcttagtcca attacaagaa ggccttgggc ttcctgtctc 159600 tagactcttt tctgcctcaa caccattcta agacccagga aattgcttgg ctcatcctca 159660 taagactgca ccagttctga gctagttgac ttgaatttcc aaacttaagt gcagcaattt 159720 gctgggacct attcccgaga atctggggct atttgaaggc agaagacagt atcaataaac 159780 ataaagcccc acagtaacta gctaaagccc cagcagataa gaggcttggg tcctacctca 159840 gaattggctc tgaatatggc aagagaagct ttaccattcc cacttcaatc agaagagtat 159900 tatagattgg gttgtagccg gagatttcat ttgaaaaaaa ggtttctatt gctttaaatg 159960 acatttggaa atctcttttc tgaaagagtt ggaatcatga ggccttgttt tcctgcactg 160020 gcatgtgaaa ctaggccagc agagcgctgg gggccagtac agctggaggt gattagctcg 160080 catctgaagt caacatagat gggagagggt ggagctggag gttgcttttt ctggaacgaa 160140 tgtcactagg aaatggaatg gggggaagaa aatgcagatt tagctttatg acctatgaat 160200 ggaaacttca tgatggtaaa tatgttactg ccctcagctg ggatctggct gcaccagcat 160260 ggaatggtat gagccacttg caagggccag tctggttaga aagcaaggtg aggccacgca 160320 gctggggtgg cacatggaaa cactcatctc aaattaatga ataagtacaa ttcagctctt 160380 aacacagctt gtattagcta agtgctagaa aatataaact gaagatatgg aatggcttaa 160440 acgtaatagt ttatttctag tttatctaac agttctggaa aagtgaacag cttggcaatc 160500 agatctactt ggctcagttt ttagcccggg ctgatgaaag tactgtaatc aacacatagc 160560 ttccaaggtt gagaatcgcc tccattcccc acgaaggatt gcctatggag aggttttacg 160620 agccaggctt acatgcaaaa cacattgctg tcactcattc catcagcaag aactggccaa 160680 atgattgcca gtgacaactc tatgctatag aaggggaagc acatattgta gtagaatata 160740 tttacaaaac tgaactcgtt attattctaa aagattgagt atcttagtgt agtcctgagc 160800 attgcagaat tagaaacaat tttatcccaa aatcaaaact tcagtgcatg tcattagtag 160860 agataattct gaattattat ggcaaacagg aaataaacag ctgttgagaa aagattcttt 160920 tacatcagtg gtcccagata gcctgccaga ttttttggtt taaaaaggac tagttatcta 160980 tatgtaatgt gataatccaa taaatttaaa aaacagctta atacacctat cttccagata 161040 cagacacctt gataatgata ggctttccat tttacataat tcagaaatat tcataattca 161100 gaaacattgt aatggtagag ataaatgtaa taaattatag gctgacctgc ataatatttt 161160 aaagccaatc gaaactttac tgtatcaatt tgggattata tttgactgca agtaagcaaa 161220 agcaaccaaa caggcctaca agttgtaaat caataagtat gtgagacatg tctcaattta 161280 gaagtttatt ttgccaaggt gaaggacatg cctggaagaa atgacatgga atcacagaaa 161340 tagtctgtgg tctgtgcctt tctccaaaga tgaatttgag ggtttcaata tttaaaggag 161400 aaaagtgagc tggaggggaa agaagagggg tatggtcaca tcactgaacc cacatgttgc 161460 aggagaaaag gagcagatag ggaa 161484 <210> SEQ ID NO 5 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Primer <400> SEQUENCE: 5 caaagtctgt tgcgagttta aatagaa 27 <210> SEQ ID NO 6 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Primer <400> SEQUENCE: 6 tacttgggat gaagagtttc cagaa 25 <210> SEQ ID NO 7 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Probe <400> SEQUENCE: 7 cattgaagac cctgggcaag catatgtt 28 <210> SEQ ID NO 8 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Primer <400> SEQUENCE: 8 gaaggtgaag gtcggagtc 19 <210> SEQ ID NO 9 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Primer <400> SEQUENCE: 9 gaagatggtg atgggatttc 20 <210> SEQ ID NO 10 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Probe <400> SEQUENCE: 10 caagcttccc gttctcagcc 20 <210> SEQ ID NO 11 <211> LENGTH: 8119 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (64)...(7521) <400> SEQUENCE: 11 cgtccctgca gccctcgccc ggcgctccag tagcaggacc cggtctcggg accagccggt 60 aat atg cac gtg tca cta gct gag gcc ctg gag gtt cgg ggt gga cca 108 Met His Val Ser Leu Ala Glu Ala Leu Glu Val Arg Gly Gly Pro 1 5 10 15 ctt cag gag gaa gaa ata tgg gct gta tta aat caa agt gct gaa agt 156 Leu Gln Glu Glu Glu Ile Trp Ala Val Leu Asn Gln Ser Ala Glu Ser 20 25 30 ctc caa gaa tta ttc aga aaa gta agc cta gct gat cct gct gcc ctt 204 Leu Gln Glu Leu Phe Arg Lys Val Ser Leu Ala Asp Pro Ala Ala Leu 35 40 45 ggc ttc atc att tct cca tgg tct ctg ctg ttg ctg cca tct ggt agt 252 Gly Phe Ile Ile Ser Pro Trp Ser Leu Leu Leu Leu Pro Ser Gly Ser 50 55 60 gtg tca ttt aca gat gaa aat att tcc aat cag gat ctt cga gca ttc 300 Val Ser Phe Thr Asp Glu Asn Ile Ser Asn Gln Asp Leu Arg Ala Phe 65 70 75 act gca cca gag gtt ctt caa aat cag tca cta act tct ctc tca gat 348 Thr Ala Pro Glu Val Leu Gln Asn Gln Ser Leu Thr Ser Leu Ser Asp 80 85 90 95 gtt gaa aag atc cac att tat tct ctt gga atg aca ctg tat tgg ggg 396 Val Glu Lys Ile His Ile Tyr Ser Leu Gly Met Thr Leu Tyr Trp Gly 100 105 110 gct gat tat gaa gtg cct cag agc caa cct att aag ctt gga gat cat 444 Ala Asp Tyr Glu Val Pro Gln Ser Gln Pro Ile Lys Leu Gly Asp His 115 120 125 ctc aac agc ata ctg ctt gga atg tgt gag gat gtt att tac gct cga 492 Leu Asn Ser Ile Leu Leu Gly Met Cys Glu Asp Val Ile Tyr Ala Arg 130 135 140 gtt tct gtt cgg act gtg ctg gat gct tgc agt gcc cac att agg aat 540 Val Ser Val Arg Thr Val Leu Asp Ala Cys Ser Ala His Ile Arg Asn 145 150 155 agc aat tgt gca ccc tca ttt tcc tac gtg aaa cac ttg gta aaa ctg 588 Ser Asn Cys Ala Pro Ser Phe Ser Tyr Val Lys His Leu Val Lys Leu 160 165 170 175 gtt ctg gga aat ctt tct ggg aca gat cag ctt tcc tgt aac agt gaa 636 Val Leu Gly Asn Leu Ser Gly Thr Asp Gln Leu Ser Cys Asn Ser Glu 180 185 190 caa aag cct gat cga agc cag gct att cga gat cga ttg cga gga aaa 684 Gln Lys Pro Asp Arg Ser Gln Ala Ile Arg Asp Arg Leu Arg Gly Lys 195 200 205 gga tta cca aca gga aga agc tct act tct gat gta cta gac ata caa 732 Gly Leu Pro Thr Gly Arg Ser Ser Thr Ser Asp Val Leu Asp Ile Gln 210 215 220 aag cct cca ctc tct cat cag acc ttt ctt aac aaa ggg ctt agt aaa 780 Lys Pro Pro Leu Ser His Gln Thr Phe Leu Asn Lys Gly Leu Ser Lys 225 230 235 tct atg gga ttt ctg tcc atc aaa gat aca caa gat gag aat tat ttc 828 Ser Met Gly Phe Leu Ser Ile Lys Asp Thr Gln Asp Glu Asn Tyr Phe 240 245 250 255 aag gac att tta tca gat aat tct gga cgt gaa gat tct gaa aat aca 876 Lys Asp Ile Leu Ser Asp Asn Ser Gly Arg Glu Asp Ser Glu Asn Thr 260 265 270 ttc tcc cct tac cag ttc aaa act agt ggc cca gaa aaa aaa ccc atc 924 Phe Ser Pro Tyr Gln Phe Lys Thr Ser Gly Pro Glu Lys Lys Pro Ile 275 280 285 cct ggc att gat gtg ctt tct aag aag aag atc tgg gct tca tcc atg 972 Pro Gly Ile Asp Val Leu Ser Lys Lys Lys Ile Trp Ala Ser Ser Met 290 295 300 gac ttg ctt tgt aca gct gac aga gac ttc tct tca gga gag act gcc 1020 Asp Leu Leu Cys Thr Ala Asp Arg Asp Phe Ser Ser Gly Glu Thr Ala 305 310 315 aca tat cgt cgt tgt cac cct gag gca gta aca gtg cgg act tca act 1068 Thr Tyr Arg Arg Cys His Pro Glu Ala Val Thr Val Arg Thr Ser Thr 320 325 330 335 act cct aga aaa aag gag gca aga tac tca gat gga agt ata gcc ttg 1116 Thr Pro Arg Lys Lys Glu Ala Arg Tyr Ser Asp Gly Ser Ile Ala Leu 340 345 350 gat atc ttt ggc cct cag aaa atg gat cca ata tat cac act cga gaa 1164 Asp Ile Phe Gly Pro Gln Lys Met Asp Pro Ile Tyr His Thr Arg Glu 355 360 365 ttg ccc acc tcc tca gca ata tca agt gct ttg gac cga atc cga gag 1212 Leu Pro Thr Ser Ser Ala Ile Ser Ser Ala Leu Asp Arg Ile Arg Glu 370 375 380 aga caa aag aaa ctt cag gtt ctg agg gaa gcc atg aat gta gaa gaa 1260 Arg Gln Lys Lys Leu Gln Val Leu Arg Glu Ala Met Asn Val Glu Glu 385 390 395 cca gtt cga aga tac aaa act tat cat ggt gat gtc ttt agt acc tcc 1308 Pro Val Arg Arg Tyr Lys Thr Tyr His Gly Asp Val Phe Ser Thr Ser 400 405 410 415 agt gaa agt cca tct att att tcc tct gaa tca gat ttc aga caa gtg 1356 Ser Glu Ser Pro Ser Ile Ile Ser Ser Glu Ser Asp Phe Arg Gln Val 420 425 430 aga aga agt gaa gcc tca aag agg ttt gaa tcc agc agt ggt ctc cca 1404 Arg Arg Ser Glu Ala Ser Lys Arg Phe Glu Ser Ser Ser Gly Leu Pro 435 440 445 ggg gta gat gaa acc tta agt caa ggc cag tca cag aga ccg agc aga 1452 Gly Val Asp Glu Thr Leu Ser Gln Gly Gln Ser Gln Arg Pro Ser Arg 450 455 460 caa tat gaa aca ccc ttt gaa ggc aac tta att aat caa gag atc atg 1500 Gln Tyr Glu Thr Pro Phe Glu Gly Asn Leu Ile Asn Gln Glu Ile Met 465 470 475 cta aaa cgg caa gag gaa gaa ctg atg cag cta caa gcc aaa atg gcc 1548 Leu Lys Arg Gln Glu Glu Glu Leu Met Gln Leu Gln Ala Lys Met Ala 480 485 490 495 ctt aga cag tct cgg ttg agc cta tat cca gga gac aca atc aaa gcg 1596 Leu Arg Gln Ser Arg Leu Ser Leu Tyr Pro Gly Asp Thr Ile Lys Ala 500 505 510 tcc atg ctt gac atc acc agg gat ccg tta aga gaa att gcc cta gaa 1644 Ser Met Leu Asp Ile Thr Arg Asp Pro Leu Arg Glu Ile Ala Leu Glu 515 520 525 aca gcc atg act caa aga aaa ctg agg aat ttc ttt ggc cct gag ttt 1692 Thr Ala Met Thr Gln Arg Lys Leu Arg Asn Phe Phe Gly Pro Glu Phe 530 535 540 gtg aaa atg aca att gaa cca ttt ata tct ttg gat ttg cca cgg tct 1740 Val Lys Met Thr Ile Glu Pro Phe Ile Ser Leu Asp Leu Pro Arg Ser 545 550 555 att ctt act aag aaa ggg aag aat gag gat aac cga agg aaa gta aac 1788 Ile Leu Thr Lys Lys Gly Lys Asn Glu Asp Asn Arg Arg Lys Val Asn 560 565 570 575 ata atg ctt ctg aac ggg caa aga ctg gaa ctg acc tgt gat acc aaa 1836 Ile Met Leu Leu Asn Gly Gln Arg Leu Glu Leu Thr Cys Asp Thr Lys 580 585 590 act ata tgt aaa gat gtg ttt gat atg gtt gtg gca cat att ggc tta 1884 Thr Ile Cys Lys Asp Val Phe Asp Met Val Val Ala His Ile Gly Leu 595 600 605 gta gag cat cat ttg ttt gct tta gct acc ctc aaa gat aat gaa tat 1932 Val Glu His His Leu Phe Ala Leu Ala Thr Leu Lys Asp Asn Glu Tyr 610 615 620 ttc ttt gtt gat cct gac tta aaa tta acc aaa gtg gcc cca gag gga 1980 Phe Phe Val Asp Pro Asp Leu Lys Leu Thr Lys Val Ala Pro Glu Gly 625 630 635 tgg aaa gaa gaa cca aag aaa aag acc aaa gcc act gtt aat ttt act 2028 Trp Lys Glu Glu Pro Lys Lys Lys Thr Lys Ala Thr Val Asn Phe Thr 640 645 650 655 ttg ttt ttc aga att aaa ttt ttt atg gat gat gtt agt cta ata caa 2076 Leu Phe Phe Arg Ile Lys Phe Phe Met Asp Asp Val Ser Leu Ile Gln 660 665 670 cat act ctg acg tgt cat cag tat tac ctt cag ctt cga aaa gat att 2124 His Thr Leu Thr Cys His Gln Tyr Tyr Leu Gln Leu Arg Lys Asp Ile 675 680 685 ttg gag gaa agg atg cac tgt gat gat gag act tcc tta ttg ctg gca 2172 Leu Glu Glu Arg Met His Cys Asp Asp Glu Thr Ser Leu Leu Leu Ala 690 695 700 tcc ttg gct ctc cag gct gag tat gga gat tat caa cca gag gtt cat 2220 Ser Leu Ala Leu Gln Ala Glu Tyr Gly Asp Tyr Gln Pro Glu Val His 705 710 715 ggt gtg tct tac ttt aga atg gag cac tat ttg ccc gcc aga gtg atg 2268 Gly Val Ser Tyr Phe Arg Met Glu His Tyr Leu Pro Ala Arg Val Met 720 725 730 735 gag aaa ctt gat tta tcc tat atc aaa gaa gag tta ccc aaa ttg cat 2316 Glu Lys Leu Asp Leu Ser Tyr Ile Lys Glu Glu Leu Pro Lys Leu His 740 745 750 aat acc tat gtg gga gct tct gaa aaa gag aca gag tta gaa ttt tta 2364 Asn Thr Tyr Val Gly Ala Ser Glu Lys Glu Thr Glu Leu Glu Phe Leu 755 760 765 aag gtc tgc caa aga ctg aca gaa tat gga gtt cat ttt cac cga gtg 2412 Lys Val Cys Gln Arg Leu Thr Glu Tyr Gly Val His Phe His Arg Val 770 775 780 cac cct gag aag aag tca caa aca gga ata ttg ctt gga gtc tgt tct 2460 His Pro Glu Lys Lys Ser Gln Thr Gly Ile Leu Leu Gly Val Cys Ser 785 790 795 aaa ggt gtc ctt gtg ttt gaa gtt cac aat gga gtg cgc aca ttg gtc 2508 Lys Gly Val Leu Val Phe Glu Val His Asn Gly Val Arg Thr Leu Val 800 805 810 815 ctt cgc ttt cca tgg agg gaa acc aag aaa ata tct ttt tct aaa aag 2556 Leu Arg Phe Pro Trp Arg Glu Thr Lys Lys Ile Ser Phe Ser Lys Lys 820 825 830 aaa atc aca ttg caa aat aca tca gat gga ata aaa cat ggc ttc cag 2604 Lys Ile Thr Leu Gln Asn Thr Ser Asp Gly Ile Lys His Gly Phe Gln 835 840 845 aca gac aac agt aag ata tgc cag tac ctg ctg cac ctc tgc tct tac 2652 Thr Asp Asn Ser Lys Ile Cys Gln Tyr Leu Leu His Leu Cys Ser Tyr 850 855 860 cag cat aag ttc cag cta cag atg aga gca aga cag agc aac caa gat 2700 Gln His Lys Phe Gln Leu Gln Met Arg Ala Arg Gln Ser Asn Gln Asp 865 870 875 gcc caa gat att gag aga gct tcg ttt agg agc ctg aat ctc caa gca 2748 Ala Gln Asp Ile Glu Arg Ala Ser Phe Arg Ser Leu Asn Leu Gln Ala 880 885 890 895 gag tct gtt aga gga ttt aat atg gga cga gca atc agc act ggc agt 2796 Glu Ser Val Arg Gly Phe Asn Met Gly Arg Ala Ile Ser Thr Gly Ser 900 905 910 ctg gcc agc agc acc ctc aac aaa ctt gct gtt cga cct tta tca gtt 2844 Leu Ala Ser Ser Thr Leu Asn Lys Leu Ala Val Arg Pro Leu Ser Val 915 920 925 caa gct gag att ctg aag agg cta tcc tgc tca gag ctg tcg ctt tac 2892 Gln Ala Glu Ile Leu Lys Arg Leu Ser Cys Ser Glu Leu Ser Leu Tyr 930 935 940 cag cca ttg caa aac agt tca aaa gag aag aat gac aaa gct tca tgg 2940 Gln Pro Leu Gln Asn Ser Ser Lys Glu Lys Asn Asp Lys Ala Ser Trp 945 950 955 gag gaa aag cct aga gag atg agt aaa tca tac cat gat ctc agt cag 2988 Glu Glu Lys Pro Arg Glu Met Ser Lys Ser Tyr His Asp Leu Ser Gln 960 965 970 975 gcc tct ctc tat cca cat cgg aaa aat gtc att gtt aac atg gaa ccc 3036 Ala Ser Leu Tyr Pro His Arg Lys Asn Val Ile Val Asn Met Glu Pro 980 985 990 cca cca caa acc gtt gca gag ttg gtg gga aaa cct tct cac cag atg 3084 Pro Pro Gln Thr Val Ala Glu Leu Val Gly Lys Pro Ser His Gln Met 995 1000 1005 tca aga tct gat gca gaa tct ttg gca gga gtg aca aaa ctt aat aat 3132 Ser Arg Ser Asp Ala Glu Ser Leu Ala Gly Val Thr Lys Leu Asn Asn 1010 1015 1020 tca aag tct gtt gcg agt tta aat aga agt cct gaa agg agg aaa cat 3180 Ser Lys Ser Val Ala Ser Leu Asn Arg Ser Pro Glu Arg Arg Lys His 1025 1030 1035 gaa tca gac tcc tca tcc att gaa gac cct ggg caa gca tat gtt cta 3228 Glu Ser Asp Ser Ser Ser Ile Glu Asp Pro Gly Gln Ala Tyr Val Leu 1040 1045 1050 1055 gga atg act atg cat agt tct gga aac tct tca tcc caa gta ccc tta 3276 Gly Met Thr Met His Ser Ser Gly Asn Ser Ser Ser Gln Val Pro Leu 1060 1065 1070 aaa gaa aat gat gtg cta cac aaa aga tgg agc ata gta tct tca cca 3324 Lys Glu Asn Asp Val Leu His Lys Arg Trp Ser Ile Val Ser Ser Pro 1075 1080 1085 gaa agg gag atc acc tta gtg aac ctg aaa aaa gat gca aag tat ggc 3372 Glu Arg Glu Ile Thr Leu Val Asn Leu Lys Lys Asp Ala Lys Tyr Gly 1090 1095 1100 ttg gga ttt caa att att ggt ggg gag aag atg gga aga ctg gac cta 3420 Leu Gly Phe Gln Ile Ile Gly Gly Glu Lys Met Gly Arg Leu Asp Leu 1105 1110 1115 ggc ata ttt atc agt tca gtt gcc cct gga gga cca gct gac ttg gat 3468 Gly Ile Phe Ile Ser Ser Val Ala Pro Gly Gly Pro Ala Asp Leu Asp 1120 1125 1130 1135 gga tgc ttg aag cca gga gac cgt ttg ata tct gtg aat agt gtg agt 3516 Gly Cys Leu Lys Pro Gly Asp Arg Leu Ile Ser Val Asn Ser Val Ser 1140 1145 1150 ctg gag gga gtc agc cac cat gct gca att gaa att ttg caa aat gca 3564 Leu Glu Gly Val Ser His His Ala Ala Ile Glu Ile Leu Gln Asn Ala 1155 1160 1165 cct gaa gat gtg aca ctt gtt atc tct cag cca aaa gaa aag ata tcc 3612 Pro Glu Asp Val Thr Leu Val Ile Ser Gln Pro Lys Glu Lys Ile Ser 1170 1175 1180 aaa gtg cct tct act cct gtg cat ctc acc aat gag atg aaa aac tac 3660 Lys Val Pro Ser Thr Pro Val His Leu Thr Asn Glu Met Lys Asn Tyr 1185 1190 1195 atg aag aaa tct tcc tac atg caa gac agt gct ata gat tct tct tcc 3708 Met Lys Lys Ser Ser Tyr Met Gln Asp Ser Ala Ile Asp Ser Ser Ser 1200 1205 1210 1215 aag gat cac cac tgg tca cgt ggt acc ctg agg cac atc tcg gag aac 3756 Lys Asp His His Trp Ser Arg Gly Thr Leu Arg His Ile Ser Glu Asn 1220 1225 1230 tcc ttt ggg cca tct ggg ggc ctg cgg gaa gga agc ctg agt tct caa 3804 Ser Phe Gly Pro Ser Gly Gly Leu Arg Glu Gly Ser Leu Ser Ser Gln 1235 1240 1245 gat tcc agg act gag agt gcc agc ttg tct caa agc cag gtc aat ggt 3852 Asp Ser Arg Thr Glu Ser Ala Ser Leu Ser Gln Ser Gln Val Asn Gly 1250 1255 1260 ttc ttt gcc agc cat tta ggt gac caa acc tgg cag gaa tca cag cat 3900 Phe Phe Ala Ser His Leu Gly Asp Gln Thr Trp Gln Glu Ser Gln His 1265 1270 1275 ggc agc cct tcc cca tct gta ata tcc aaa gcc acc gag aaa gag act 3948 Gly Ser Pro Ser Pro Ser Val Ile Ser Lys Ala Thr Glu Lys Glu Thr 1280 1285 1290 1295 ttc act gat agt aac caa agc aaa act aaa aag cca ggc att tct gat 3996 Phe Thr Asp Ser Asn Gln Ser Lys Thr Lys Lys Pro Gly Ile Ser Asp 1300 1305 1310 gta act gat tac tca gac cgt gga gat tca gac atg gat gaa gcc act 4044 Val Thr Asp Tyr Ser Asp Arg Gly Asp Ser Asp Met Asp Glu Ala Thr 1315 1320 1325 tac tcc agc agt cag gat cat caa aca cca aaa cag gaa tct tcc tct 4092 Tyr Ser Ser Ser Gln Asp His Gln Thr Pro Lys Gln Glu Ser Ser Ser 1330 1335 1340 tca gtg aat aca tcc aac aag atg aat ttt aaa act ttt tct tca tca 4140 Ser Val Asn Thr Ser Asn Lys Met Asn Phe Lys Thr Phe Ser Ser Ser 1345 1350 1355 cct cct aag cct gga gat atc ttt gag gtt gaa ctg gct aaa aat gat 4188 Pro Pro Lys Pro Gly Asp Ile Phe Glu Val Glu Leu Ala Lys Asn Asp 1360 1365 1370 1375 aac agc ttg ggg ata agt gtc acg gga ggt gtg aat acg agt gtc aga 4236 Asn Ser Leu Gly Ile Ser Val Thr Gly Gly Val Asn Thr Ser Val Arg 1380 1385 1390 cat ggt ggc att tat gtg aaa gct gtt att ccc cag gga gca gca gag 4284 His Gly Gly Ile Tyr Val Lys Ala Val Ile Pro Gln Gly Ala Ala Glu 1395 1400 1405 tct gat ggt aga att cac aaa ggt gat cgc gtc cta gct gtc aat gga 4332 Ser Asp Gly Arg Ile His Lys Gly Asp Arg Val Leu Ala Val Asn Gly 1410 1415 1420 gtt agt cta gaa gga gcc acc cat aag caa gct gtg gaa aca ctg aga 4380 Val Ser Leu Glu Gly Ala Thr His Lys Gln Ala Val Glu Thr Leu Arg 1425 1430 1435 aat aca gga cag gtg gtt cat ctg tta tta gaa aag gga caa tct cca 4428 Asn Thr Gly Gln Val Val His Leu Leu Leu Glu Lys Gly Gln Ser Pro 1440 1445 1450 1455 aca tct aaa gaa cat gtc ccg gta acc cca cag tgt acc ctt tca gat 4476 Thr Ser Lys Glu His Val Pro Val Thr Pro Gln Cys Thr Leu Ser Asp 1460 1465 1470 cag aat gcc caa ggt caa ggc cca gaa aaa gtg aag aaa aca act cag 4524 Gln Asn Ala Gln Gly Gln Gly Pro Glu Lys Val Lys Lys Thr Thr Gln 1475 1480 1485 gtc aaa gac tac agc ttt gtc act gaa gaa aat aca ttt gag gta aaa 4572 Val Lys Asp Tyr Ser Phe Val Thr Glu Glu Asn Thr Phe Glu Val Lys 1490 1495 1500 tta ttt aaa aat agc tca ggt cta gga ttc agt ttt tct cga gaa gat 4620 Leu Phe Lys Asn Ser Ser Gly Leu Gly Phe Ser Phe Ser Arg Glu Asp 1505 1510 1515 aat ctt ata ccg gag caa att aat gcc agc ata gta agg gtt aaa aag 4668 Asn Leu Ile Pro Glu Gln Ile Asn Ala Ser Ile Val Arg Val Lys Lys 1520 1525 1530 1535 ctc ttt cct gga cag cca gca gca gaa agt gga aaa att gat gta gga 4716 Leu Phe Pro Gly Gln Pro Ala Ala Glu Ser Gly Lys Ile Asp Val Gly 1540 1545 1550 gat gtt atc ttg aaa gtg aat gga gcc tct ttg aaa gga cta tct cag 4764 Asp Val Ile Leu Lys Val Asn Gly Ala Ser Leu Lys Gly Leu Ser Gln 1555 1560 1565 cag gaa gtc ata tct gct ctc agg gga act gct cca gaa gta ttc ttg 4812 Gln Glu Val Ile Ser Ala Leu Arg Gly Thr Ala Pro Glu Val Phe Leu 1570 1575 1580 ctt ctc tgc aga cct cca cct ggt gtg cta ccg gaa att gat act gcg 4860 Leu Leu Cys Arg Pro Pro Pro Gly Val Leu Pro Glu Ile Asp Thr Ala 1585 1590 1595 ctt ttg acc cca ctt cag tct cca gca caa gta ctt cca aac agc agt 4908 Leu Leu Thr Pro Leu Gln Ser Pro Ala Gln Val Leu Pro Asn Ser Ser 1600 1605 1610 1615 aaa gac tct tct cag cca tca tgt gtg gag caa agc acc agc tca gat 4956 Lys Asp Ser Ser Gln Pro Ser Cys Val Glu Gln Ser Thr Ser Ser Asp 1620 1625 1630 gaa aat gaa atg tca gac aaa agc aaa aaa cag tgc aag tcc cca tcc 5004 Glu Asn Glu Met Ser Asp Lys Ser Lys Lys Gln Cys Lys Ser Pro Ser 1635 1640 1645 aga aga gac agt tac agt gac agc agt ggg agt gga gaa gat gac tta 5052 Arg Arg Asp Ser Tyr Ser Asp Ser Ser Gly Ser Gly Glu Asp Asp Leu 1650 1655 1660 gtg aca gct cca gca aac ata tca aat tcg acc tgg agt tca gct ttg 5100 Val Thr Ala Pro Ala Asn Ile Ser Asn Ser Thr Trp Ser Ser Ala Leu 1665 1670 1675 cat cag act cta agc aac atg gta tca cag gca cag agt cat cat gaa 5148 His Gln Thr Leu Ser Asn Met Val Ser Gln Ala Gln Ser His His Glu 1680 1685 1690 1695 gca ccc aag agt caa gaa gat acc att tgt acc atg ttt tac tat cct 5196 Ala Pro Lys Ser Gln Glu Asp Thr Ile Cys Thr Met Phe Tyr Tyr Pro 1700 1705 1710 cag aaa att ccc aat aaa cca gag ttt gag gac agt aat cct tcc cct 5244 Gln Lys Ile Pro Asn Lys Pro Glu Phe Glu Asp Ser Asn Pro Ser Pro 1715 1720 1725 cta cca ccg gat atg gct cct ggg cag agt tat caa ccc caa tca gaa 5292 Leu Pro Pro Asp Met Ala Pro Gly Gln Ser Tyr Gln Pro Gln Ser Glu 1730 1735 1740 tct gct tcc tct agt tcg atg gat aag tat cat ata cat cac att tct 5340 Ser Ala Ser Ser Ser Ser Met Asp Lys Tyr His Ile His His Ile Ser 1745 1750 1755 gaa cca act aga caa gaa aac tgg aca cct ttg aaa aat gac ttg gaa 5388 Glu Pro Thr Arg Gln Glu Asn Trp Thr Pro Leu Lys Asn Asp Leu Glu 1760 1765 1770 1775 aat cac ctt gaa gac ttt gaa ctg gaa gta gaa ctc ctc att acc cta 5436 Asn His Leu Glu Asp Phe Glu Leu Glu Val Glu Leu Leu Ile Thr Leu 1780 1785 1790 att aaa tca gaa aaa gga agc ctg ggt ttt aca gta acc aaa ggc aat 5484 Ile Lys Ser Glu Lys Gly Ser Leu Gly Phe Thr Val Thr Lys Gly Asn 1795 1800 1805 cag aga att ggt tgt tat gtt cat gat gtc ata cag gat cca gcc aaa 5532 Gln Arg Ile Gly Cys Tyr Val His Asp Val Ile Gln Asp Pro Ala Lys 1810 1815 1820 agt gat gga agg cta aaa cct ggg gac cgg ctc ata aag gtt aat gat 5580 Ser Asp Gly Arg Leu Lys Pro Gly Asp Arg Leu Ile Lys Val Asn Asp 1825 1830 1835 aca gat gtt act aat atg act cat aca gat gca gtt aat ctg ctc cgg 5628 Thr Asp Val Thr Asn Met Thr His Thr Asp Ala Val Asn Leu Leu Arg 1840 1845 1850 1855 gct gca tcc aaa aca gtc aga tta gtt att gga cga gtt cta gaa tta 5676 Ala Ala Ser Lys Thr Val Arg Leu Val Ile Gly Arg Val Leu Glu Leu 1860 1865 1870 ccc aga ata cca atg ttg cct cat ttg cta ccg gac ata aca cta acg 5724 Pro Arg Ile Pro Met Leu Pro His Leu Leu Pro Asp Ile Thr Leu Thr 1875 1880 1885 tgc aac aaa gag gag ttg ggt ttt tcc tta tgt gga ggt cat gac agc 5772 Cys Asn Lys Glu Glu Leu Gly Phe Ser Leu Cys Gly Gly His Asp Ser 1890 1895 1900 ctt tat caa gtg gta tat att agt gat att aat cca agg tcc gtc gca 5820 Leu Tyr Gln Val Val Tyr Ile Ser Asp Ile Asn Pro Arg Ser Val Ala 1905 1910 1915 gcc att gag ggt aat ctc cag cta tta gat gtc atc cat tat gtg aac 5868 Ala Ile Glu Gly Asn Leu Gln Leu Leu Asp Val Ile His Tyr Val Asn 1920 1925 1930 1935 gga gtc agc aca caa gga atg acc ttg gag gaa gtt aac aga gca tta 5916 Gly Val Ser Thr Gln Gly Met Thr Leu Glu Glu Val Asn Arg Ala Leu 1940 1945 1950 gac atg tca ctt cct tca ttg gta ttg aaa gca aca aga aat gat ctt 5964 Asp Met Ser Leu Pro Ser Leu Val Leu Lys Ala Thr Arg Asn Asp Leu 1955 1960 1965 cca gtg gtc ccc agc tca aag agg tct gct gtt tca gct cca aag tca 6012 Pro Val Val Pro Ser Ser Lys Arg Ser Ala Val Ser Ala Pro Lys Ser 1970 1975 1980 acc aaa ggc aat ggt tcc tac agt gtg ggg tct tgc agc cag cct gcc 6060 Thr Lys Gly Asn Gly Ser Tyr Ser Val Gly Ser Cys Ser Gln Pro Ala 1985 1990 1995 ctc act cct aat gat tca ttc tcc acg gtt gct ggg gaa gaa ata aat 6108 Leu Thr Pro Asn Asp Ser Phe Ser Thr Val Ala Gly Glu Glu Ile Asn 2000 2005 2010 2015 gaa ata tcg tac ccc aaa gga aaa tgt tct act tat cag ata aag gga 6156 Glu Ile Ser Tyr Pro Lys Gly Lys Cys Ser Thr Tyr Gln Ile Lys Gly 2020 2025 2030 tca cca aac ttg act ctg ccc aaa gaa tct tat ata caa gaa gat gac 6204 Ser Pro Asn Leu Thr Leu Pro Lys Glu Ser Tyr Ile Gln Glu Asp Asp 2035 2040 2045 att tat gat gat tcc caa gaa gct gaa gtt atc cag tct ctg ctg gat 6252 Ile Tyr Asp Asp Ser Gln Glu Ala Glu Val Ile Gln Ser Leu Leu Asp 2050 2055 2060 gtt gtg gat gag gaa gcc cag aat ctt tta aac gaa aat aat gca gca 6300 Val Val Asp Glu Glu Ala Gln Asn Leu Leu Asn Glu Asn Asn Ala Ala 2065 2070 2075 gga tac tcc tgt ggt cca ggt aca tta aag atg aat ggg aag tta tca 6348 Gly Tyr Ser Cys Gly Pro Gly Thr Leu Lys Met Asn Gly Lys Leu Ser 2080 2085 2090 2095 gaa gag aga aca gaa gat aca gac tgc gat ggt tca cct tta cct gag 6396 Glu Glu Arg Thr Glu Asp Thr Asp Cys Asp Gly Ser Pro Leu Pro Glu 2100 2105 2110 tat ttt act gag gcc acc aaa atg aat ggc tgt gaa gaa tat tgt gaa 6444 Tyr Phe Thr Glu Ala Thr Lys Met Asn Gly Cys Glu Glu Tyr Cys Glu 2115 2120 2125 gaa aaa gta aaa agt gaa agc tta att cag aag cca caa gaa aag aag 6492 Glu Lys Val Lys Ser Glu Ser Leu Ile Gln Lys Pro Gln Glu Lys Lys 2130 2135 2140 act gat gat gat gaa ata aca tgg gga aat gat gag ttg cca ata gag 6540 Thr Asp Asp Asp Glu Ile Thr Trp Gly Asn Asp Glu Leu Pro Ile Glu 2145 2150 2155 aga aca aac cat gaa gat tct gat aaa gat cat tcc ttt ctg aca aac 6588 Arg Thr Asn His Glu Asp Ser Asp Lys Asp His Ser Phe Leu Thr Asn 2160 2165 2170 2175 gat gag ctc gct gta ctc cct gtc gtc aaa gtg ctt ccc tct ggt aaa 6636 Asp Glu Leu Ala Val Leu Pro Val Val Lys Val Leu Pro Ser Gly Lys 2180 2185 2190 tac acg ggt gcc aac tta aaa tca gtc att cga gtc ctg cgg ggt ttg 6684 Tyr Thr Gly Ala Asn Leu Lys Ser Val Ile Arg Val Leu Arg Gly Leu 2195 2200 2205 cta gat caa gga att cct tct aag gag ctg gag aat ctt caa gaa tta 6732 Leu Asp Gln Gly Ile Pro Ser Lys Glu Leu Glu Asn Leu Gln Glu Leu 2210 2215 2220 aaa cct ttg gat cag tgt cta att ggg caa act aag gaa aac aga agg 6780 Lys Pro Leu Asp Gln Cys Leu Ile Gly Gln Thr Lys Glu Asn Arg Arg 2225 2230 2235 aag aac aga tat aaa aat ata ctt ccc tat gat gct aca aga gtg cct 6828 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Tyr Asp Ala Thr Arg Val Pro 2240 2245 2250 2255 ctt gga gat gaa ggt ggc tat atc aat gcc agc ttc att aag ata cca 6876 Leu Gly Asp Glu Gly Gly Tyr Ile Asn Ala Ser Phe Ile Lys Ile Pro 2260 2265 2270 gtt ggg aaa gaa gag ttc gtt tac att gcc tgc caa gga cca ctg cct 6924 Val Gly Lys Glu Glu Phe Val Tyr Ile Ala Cys Gln Gly Pro Leu Pro 2275 2280 2285 aca act gtt gga gac ttc tgg cag atg att tgg gag caa aaa tcc aca 6972 Thr Thr Val Gly Asp Phe Trp Gln Met Ile Trp Glu Gln Lys Ser Thr 2290 2295 2300 gtg ata gcc atg atg act caa gaa gta gaa gga gaa aaa atc aaa tgc 7020 Val Ile Ala Met Met Thr Gln Glu Val Glu Gly Glu Lys Ile Lys Cys 2305 2310 2315 cag cgc tat tgg ccc aac atc cta ggc aaa aca aca atg gtc agc aac 7068 Gln Arg Tyr Trp Pro Asn Ile Leu Gly Lys Thr Thr Met Val Ser Asn 2320 2325 2330 2335 aga ctt cga ctg gct ctt gtg aga atg cag cag ctg aag ggc ttt gtg 7116 Arg Leu Arg Leu Ala Leu Val Arg Met Gln Gln Leu Lys Gly Phe Val 2340 2345 2350 gtg agg gca atg acc ctt gaa gat att cag acc aga gag gtg cgc cat 7164 Val Arg Ala Met Thr Leu Glu Asp Ile Gln Thr Arg Glu Val Arg His 2355 2360 2365 att tct cat ctg aat ttc act gcc tgg cca gac cat gat aca cct tct 7212 Ile Ser His Leu Asn Phe Thr Ala Trp Pro Asp His Asp Thr Pro Ser 2370 2375 2380 caa cca gat gat ctg ctt act ttt atc tcc tac atg aga cac atc cac 7260 Gln Pro Asp Asp Leu Leu Thr Phe Ile Ser Tyr Met Arg His Ile His 2385 2390 2395 aga tca ggc cca atc att acg cac tgc agt gct ggc att gga cgt tca 7308 Arg Ser Gly Pro Ile Ile Thr His Cys Ser Ala Gly Ile Gly Arg Ser 2400 2405 2410 2415 ggg acc ctg att tgc ata gat gtg gtt ctg gga tta atc agt cag gat 7356 Gly Thr Leu Ile Cys Ile Asp Val Val Leu Gly Leu Ile Ser Gln Asp 2420 2425 2430 ctt gat ttt gac atc tct gat ttg gtg cgc tgc atg aga cta caa aga 7404 Leu Asp Phe Asp Ile Ser Asp Leu Val Arg Cys Met Arg Leu Gln Arg 2435 2440 2445 cac gga atg gtt cag aca gag gat caa tat att ttc tgc tat caa gtc 7452 His Gly Met Val Gln Thr Glu Asp Gln Tyr Ile Phe Cys Tyr Gln Val 2450 2455 2460 atc ctt tat gtc ctg aca cgt ctt caa gca gaa gaa gag caa aaa cag 7500 Ile Leu Tyr Val Leu Thr Arg Leu Gln Ala Glu Glu Glu Gln Lys Gln 2465 2470 2475 cag cct cag ctt ctg aag tga catgaaaaga gcctctggat gcatttccat 7551 Gln Pro Gln Leu Leu Lys 2480 2485 ttctctcctt aacctccagc agactcctgc tctctatcca aaataaagat cacagagcag 7611 caagttcata caacatgcat gttctcctct atcttagagg ggtattcttc ttgaaaataa 7671 aaaatattga aatgctgtat ttttacagct actttaacct atgataatta tttacaaaat 7731 tttaacacta accaaacaat gcagatctta gggatgatta aaggcagcat ttgatgatag 7791 cagacattgt tacaaggaca tggtgagtct atttttaatg caccaatctt gtttatagca 7851 aaaatgtttt ccaatatttt aataaagtag ttattttata ggggatactt gaaaccagta 7911 tttaagcttt aaatgacagt aatattggca tagaaaaaag tagcaaatgt ttactgtatc 7971 aatttctaat gtttactata tagaatttcc tgtaatatat ttatatactt tttcatgaaa 8031 atggagttat cagttatctg tttgttactg catcatctgt ttgtaatcat tatctcactt 8091 tgtaaataaa aacacacctt aaaacatg 8119 <210> SEQ ID NO 12 <211> LENGTH: 8287 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (218)...(7690) <400> SEQUENCE: 12 ctgattatga agtgcctcag agccaaccta ttaagcttgg agatcatctc aacagcatac 60 tgcttggaat gtgtgaggat gttatttacg ctcgagtttc tgttcggact gtgctggatg 120 cttgcagtgc ccacattagg aatagcaatt gtgcaccctc attttcctac gtgaaacact 180 tggtaaaact ggttctggga aatctttctg gggtaat atg cac gtg tca cta gct 235 Met His Val Ser Leu Ala 1 5 gag gcc ctg gag gtt cgg ggt gga cca ctt cag gag gaa gaa ata tgg 283 Glu Ala Leu Glu Val Arg Gly Gly Pro Leu Gln Glu Glu Glu Ile Trp 10 15 20 gct gta tta aat caa agt gct gaa agt ctc caa gaa tta ttc aga aaa 331 Ala Val Leu Asn Gln Ser Ala Glu Ser Leu Gln Glu Leu Phe Arg Lys 25 30 35 gta agc cta gct gat cct gct gcc ctt ggc ttc atc att tct cca tgg 379 Val Ser Leu Ala Asp Pro Ala Ala Leu Gly Phe Ile Ile Ser Pro Trp 40 45 50 tct ctg ctg ttg ctg cca tct ggt agt gtg tca ttt aca gat gaa aat 427 Ser Leu Leu Leu Leu Pro Ser Gly Ser Val Ser Phe Thr Asp Glu Asn 55 60 65 70 att tcc aat cag gat ctt cga gca ttc act gca cca gag gtt ctt caa 475 Ile Ser Asn Gln Asp Leu Arg Ala Phe Thr Ala Pro Glu Val Leu Gln 75 80 85 aat cag tca cta act tct ctc tca gat gtt gaa aag atc cac att tat 523 Asn Gln Ser Leu Thr Ser Leu Ser Asp Val Glu Lys Ile His Ile Tyr 90 95 100 tct ctt gga atg aca ctg tat tgg ggg gct gat tat gaa gtg cct cag 571 Ser Leu Gly Met Thr Leu Tyr Trp Gly Ala Asp Tyr Glu Val Pro Gln 105 110 115 agc caa cct att aag ctt gga gat cat ctc aac agc ata ctg ctt gga 619 Ser Gln Pro Ile Lys Leu Gly Asp His Leu Asn Ser Ile Leu Leu Gly 120 125 130 atg tgt gag gat gtt att tac gct cga gtt tct gtt cgg act gtg ctg 667 Met Cys Glu Asp Val Ile Tyr Ala Arg Val Ser Val Arg Thr Val Leu 135 140 145 150 gat gct tgc agt gcc cac att agg aat agc aat tgt gca ccc tca ttt 715 Asp Ala Cys Ser Ala His Ile Arg Asn Ser Asn Cys Ala Pro Ser Phe 155 160 165 tcc tac gtg aaa cac ttg gta aaa ctg gtt ctg gga aat ctt tct ggg 763 Ser Tyr Val Lys His Leu Val Lys Leu Val Leu Gly Asn Leu Ser Gly 170 175 180 aca gat cag ctt tcc tgt aac agt gaa caa aag cct gat cga agc cag 811 Thr Asp Gln Leu Ser Cys Asn Ser Glu Gln Lys Pro Asp Arg Ser Gln 185 190 195 gct att cga gat cga ttg cga gga aaa gga tta cca aca gga aga agc 859 Ala Ile Arg Asp Arg Leu Arg Gly Lys Gly Leu Pro Thr Gly Arg Ser 200 205 210 tct act tct gat gta cta gac ata caa aag cct cca ctc tct cat cag 907 Ser Thr Ser Asp Val Leu Asp Ile Gln Lys Pro Pro Leu Ser His Gln 215 220 225 230 acc ttt ctt aac aaa ggg ctt agt aaa tct atg gga ttt ctg tcc atc 955 Thr Phe Leu Asn Lys Gly Leu Ser Lys Ser Met Gly Phe Leu Ser Ile 235 240 245 aaa gat aca caa gat gag aat tat ttc aag gac att tta tca gat aat 1003 Lys Asp Thr Gln Asp Glu Asn Tyr Phe Lys Asp Ile Leu Ser Asp Asn 250 255 260 tct gga cgt gaa gat tct gaa aat aca ttc tcc cct tac cag ttc aaa 1051 Ser Gly Arg Glu Asp Ser Glu Asn Thr Phe Ser Pro Tyr Gln Phe Lys 265 270 275 act agt ggc cca gaa aaa aaa ccc atc cct ggc att gat gtg ctt tct 1099 Thr Ser Gly Pro Glu Lys Lys Pro Ile Pro Gly Ile Asp Val Leu Ser 280 285 290 aag aag aag atc tgg gct tca tcc atg gac ttg ctt tgt aca gct gac 1147 Lys Lys Lys Ile Trp Ala Ser Ser Met Asp Leu Leu Cys Thr Ala Asp 295 300 305 310 aga gac ttc tct tca gga gag act gcc aca tat cgt cgt tgt cac cct 1195 Arg Asp Phe Ser Ser Gly Glu Thr Ala Thr Tyr Arg Arg Cys His Pro 315 320 325 gag gca gta aca gtg cgg act tca act act cct aga aaa aag gag gca 1243 Glu Ala Val Thr Val Arg Thr Ser Thr Thr Pro Arg Lys Lys Glu Ala 330 335 340 aga tac tca gat gga agt ata gcc ttg gat atc ttt ggc cct cag aaa 1291 Arg Tyr Ser Asp Gly Ser Ile Ala Leu Asp Ile Phe Gly Pro Gln Lys 345 350 355 atg gat cca ata tat cac act cga gaa ttg ccc acc tcc tca gca ata 1339 Met Asp Pro Ile Tyr His Thr Arg Glu Leu Pro Thr Ser Ser Ala Ile 360 365 370 tca agt gct ttg gac cga atc cga gag aga caa aag aaa ctt cag gtt 1387 Ser Ser Ala Leu Asp Arg Ile Arg Glu Arg Gln Lys Lys Leu Gln Val 375 380 385 390 ctg agg gaa gcc atg aat gta gaa gaa cca gtt cga aga tac aaa act 1435 Leu Arg Glu Ala Met Asn Val Glu Glu Pro Val Arg Arg Tyr Lys Thr 395 400 405 tat cat ggt gat gtc ttt agt acc tcc agt gaa agt cca tct att att 1483 Tyr His Gly Asp Val Phe Ser Thr Ser Ser Glu Ser Pro Ser Ile Ile 410 415 420 tcc tct gaa tca gat ttc aga caa gtg aga aga agt gaa gcc tca aag 1531 Ser Ser Glu Ser Asp Phe Arg Gln Val Arg Arg Ser Glu Ala Ser Lys 425 430 435 agg ttt gaa tcc agc agt ggt ctc cca ggg gta gat gaa acc tta agt 1579 Arg Phe Glu Ser Ser Ser Gly Leu Pro Gly Val Asp Glu Thr Leu Ser 440 445 450 caa ggc cag tca cag aga ccg agc aga caa tat gaa aca ccc ttt gaa 1627 Gln Gly Gln Ser Gln Arg Pro Ser Arg Gln Tyr Glu Thr Pro Phe Glu 455 460 465 470 ggc aac tta att aat caa gag atc atg cta aaa cgg caa gag gaa gaa 1675 Gly Asn Leu Ile Asn Gln Glu Ile Met Leu Lys Arg Gln Glu Glu Glu 475 480 485 ctg atg cag cta caa gcc aaa atg gcc ctt aga cag tct cgg ttg agc 1723 Leu Met Gln Leu Gln Ala Lys Met Ala Leu Arg Gln Ser Arg Leu Ser 490 495 500 cta tat cca gga gac aca atc aaa gcg tcc atg ctt gac atc acc agg 1771 Leu Tyr Pro Gly Asp Thr Ile Lys Ala Ser Met Leu Asp Ile Thr Arg 505 510 515 gat ccg tta aga gaa att gcc cta gaa aca gcc atg act caa aga aaa 1819 Asp Pro Leu Arg Glu Ile Ala Leu Glu Thr Ala Met Thr Gln Arg Lys 520 525 530 ctg agg aat ttc ttt ggc cct gag ttt gtg aaa atg aca att gaa cca 1867 Leu Arg Asn Phe Phe Gly Pro Glu Phe Val Lys Met Thr Ile Glu Pro 535 540 545 550 ttt ata tct ttg gat ttg cca cgg tct att ctt act aag aaa ggg aag 1915 Phe Ile Ser Leu Asp Leu Pro Arg Ser Ile Leu Thr Lys Lys Gly Lys 555 560 565 aat gag gat aac cga agg aaa gta aac ata atg ctt ctg aac ggg caa 1963 Asn Glu Asp Asn Arg Arg Lys Val Asn Ile Met Leu Leu Asn Gly Gln 570 575 580 aga ctg gaa ctg acc tgt gat acc aaa act ata tgt aaa gat gtg ttt 2011 Arg Leu Glu Leu Thr Cys Asp Thr Lys Thr Ile Cys Lys Asp Val Phe 585 590 595 gat atg gtt gtg gca cat att ggc tta gta gag cat cat ttg ttt gct 2059 Asp Met Val Val Ala His Ile Gly Leu Val Glu His His Leu Phe Ala 600 605 610 tta gct acc ctc aaa gat aat gaa tat ttc ttt gtt gat cct gac tta 2107 Leu Ala Thr Leu Lys Asp Asn Glu Tyr Phe Phe Val Asp Pro Asp Leu 615 620 625 630 aaa tta acc aaa gtg gcc cca gag gga tgg aaa gaa gaa cca aag aaa 2155 Lys Leu Thr Lys Val Ala Pro Glu Gly Trp Lys Glu Glu Pro Lys Lys 635 640 645 aag acc aaa gcc act gtt aat ttt act ttg ttt ttc aga att aaa ttt 2203 Lys Thr Lys Ala Thr Val Asn Phe Thr Leu Phe Phe Arg Ile Lys Phe 650 655 660 ttt atg gat gat gtt agt cta ata caa cat act ctg acg tgt cat cag 2251 Phe Met Asp Asp Val Ser Leu Ile Gln His Thr Leu Thr Cys His Gln 665 670 675 tat tac ctt cag ctt cga aaa gat att ttg gag gaa agg atg cac tgt 2299 Tyr Tyr Leu Gln Leu Arg Lys Asp Ile Leu Glu Glu Arg Met His Cys 680 685 690 gat gat gag act tcc tta ttg ctg gca tcc ttg gct ctc cag gct gag 2347 Asp Asp Glu Thr Ser Leu Leu Leu Ala Ser Leu Ala Leu Gln Ala Glu 695 700 705 710 tat gga gat tat caa cca gag gtt cat ggt gtg tct tac ttt aga atg 2395 Tyr Gly Asp Tyr Gln Pro Glu Val His Gly Val Ser Tyr Phe Arg Met 715 720 725 gag cac tat ttg ccc gcc aga gtg atg gag aaa ctt gat tta tcc tat 2443 Glu His Tyr Leu Pro Ala Arg Val Met Glu Lys Leu Asp Leu Ser Tyr 730 735 740 atc aaa gaa gag tta ccc aaa ttg cat aat acc tat gtg gga gct tct 2491 Ile Lys Glu Glu Leu Pro Lys Leu His Asn Thr Tyr Val Gly Ala Ser 745 750 755 gaa aaa gag aca gag tta gaa ttt tta aag gtc tgc caa aga ctg aca 2539 Glu Lys Glu Thr Glu Leu Glu Phe Leu Lys Val Cys Gln Arg Leu Thr 760 765 770 gaa tat gga gtt cat ttt cac cga gtg cac cct gag aag aag tca caa 2587 Glu Tyr Gly Val His Phe His Arg Val His Pro Glu Lys Lys Ser Gln 775 780 785 790 aca gga ata ttg ctt gga gtc tgt tct aaa ggt gtc ctt gtg ttt gaa 2635 Thr Gly Ile Leu Leu Gly Val Cys Ser Lys Gly Val Leu Val Phe Glu 795 800 805 gtt cac aat gga gtg cgc aca ttg gtc ctt cgc ttt cca tgg agg gaa 2683 Val His Asn Gly Val Arg Thr Leu Val Leu Arg Phe Pro Trp Arg Glu 810 815 820 acc aag aaa ata tct ttt tct aaa aag aaa atc aca ttg caa aat aca 2731 Thr Lys Lys Ile Ser Phe Ser Lys Lys Lys Ile Thr Leu Gln Asn Thr 825 830 835 tca gat gga ata aaa cat ggc ttc cag aca gac aac agt aag ata tgc 2779 Ser Asp Gly Ile Lys His Gly Phe Gln Thr Asp Asn Ser Lys Ile Cys 840 845 850 cag tac ctg ctg cac ctc tgc tct tac cag cat aag ttc cag cta cag 2827 Gln Tyr Leu Leu His Leu Cys Ser Tyr Gln His Lys Phe Gln Leu Gln 855 860 865 870 atg aga gca aga cag agc aac caa gat gcc caa gat att gag aga gct 2875 Met Arg Ala Arg Gln Ser Asn Gln Asp Ala Gln Asp Ile Glu Arg Ala 875 880 885 tcg ttt agg agc ctg aat ctc caa gca gag tct gtt aga gga ttt aat 2923 Ser Phe Arg Ser Leu Asn Leu Gln Ala Glu Ser Val Arg Gly Phe Asn 890 895 900 atg gga cga gca atc agc act ggc agt ctg gcc agc agc acc ctc aac 2971 Met Gly Arg Ala Ile Ser Thr Gly Ser Leu Ala Ser Ser Thr Leu Asn 905 910 915 aaa ctt gct gtt cga cct tta tca gtt caa gct gag att ctg aag agg 3019 Lys Leu Ala Val Arg Pro Leu Ser Val Gln Ala Glu Ile Leu Lys Arg 920 925 930 cta tcc tgc tca gag ctg tcg ctt tac cag cca ttg caa aac agt tca 3067 Leu Ser Cys Ser Glu Leu Ser Leu Tyr Gln Pro Leu Gln Asn Ser Ser 935 940 945 950 aaa gag aag aat gac aaa gct tca tgg gag gaa aag cct aga gag atg 3115 Lys Glu Lys Asn Asp Lys Ala Ser Trp Glu Glu Lys Pro Arg Glu Met 955 960 965 agt aaa tca tac cat gat ctc agt cag gcc tct ctc tat cca cat cgg 3163 Ser Lys Ser Tyr His Asp Leu Ser Gln Ala Ser Leu Tyr Pro His Arg 970 975 980 aaa aat gtc att gtt aac atg gaa ccc cca cca caa acc gtt gca gag 3211 Lys Asn Val Ile Val Asn Met Glu Pro Pro Pro Gln Thr Val Ala Glu 985 990 995 ttg gtg gga aaa cct tct cac cag atg tca aga tct gat gca gaa tct 3259 Leu Val Gly Lys Pro Ser His Gln Met Ser Arg Ser Asp Ala Glu Ser 1000 1005 1010 ttg gca gga gtg aca aaa ctt aat aat tca aag tct gtt gcg agt tta 3307 Leu Ala Gly Val Thr Lys Leu Asn Asn Ser Lys Ser Val Ala Ser Leu 1015 1020 1025 1030 aat aga agt cct gaa agg agg aaa cat gaa tca gac tcc tca tcc att 3355 Asn Arg Ser Pro Glu Arg Arg Lys His Glu Ser Asp Ser Ser Ser Ile 1035 1040 1045 gaa gac cct ggg caa gca tat gtt cta gga atg act atg cat agt tct 3403 Glu Asp Pro Gly Gln Ala Tyr Val Leu Gly Met Thr Met His Ser Ser 1050 1055 1060 gga aac tct tca tcc caa gta ccc tta aaa gaa aat gat gtg cta cac 3451 Gly Asn Ser Ser Ser Gln Val Pro Leu Lys Glu Asn Asp Val Leu His 1065 1070 1075 aaa aga tgg agc ata gta tct tca cca gaa agg gag atc acc tta gtg 3499 Lys Arg Trp Ser Ile Val Ser Ser Pro Glu Arg Glu Ile Thr Leu Val 1080 1085 1090 aac ctg aaa aaa gat gca aag tat ggc ttg gga ttt caa att att ggt 3547 Asn Leu Lys Lys Asp Ala Lys Tyr Gly Leu Gly Phe Gln Ile Ile Gly 1095 1100 1105 1110 ggg gag aag atg gga aga ctg gac cta ggc ata ttt atc agt tca gtt 3595 Gly Glu Lys Met Gly Arg Leu Asp Leu Gly Ile Phe Ile Ser Ser Val 1115 1120 1125 gcc cct gga gga cca gct gac ttg gat gga tgc ttg aag cca gga gac 3643 Ala Pro Gly Gly Pro Ala Asp Leu Asp Gly Cys Leu Lys Pro Gly Asp 1130 1135 1140 cgt ttg ata tct gtg aat agt gtg agt ctg gag gga gtc agc cac cat 3691 Arg Leu Ile Ser Val Asn Ser Val Ser Leu Glu Gly Val Ser His His 1145 1150 1155 gct gca att gaa att ttg caa aat gca cct gaa gat gtg aca ctt gtt 3739 Ala Ala Ile Glu Ile Leu Gln Asn Ala Pro Glu Asp Val Thr Leu Val 1160 1165 1170 atc tct cag cca aaa gaa aag ata tcc aaa gtg cct tct act cct gtg 3787 Ile Ser Gln Pro Lys Glu Lys Ile Ser Lys Val Pro Ser Thr Pro Val 1175 1180 1185 1190 cat ctc acc aat gag atg aaa aac tac atg aag aaa tct tcc tac atg 3835 His Leu Thr Asn Glu Met Lys Asn Tyr Met Lys Lys Ser Ser Tyr Met 1195 1200 1205 caa gac agt gct ata gat tct tct tcc aag gat cac cac tgg tca cgt 3883 Gln Asp Ser Ala Ile Asp Ser Ser Ser Lys Asp His His Trp Ser Arg 1210 1215 1220 ggt acc ctg agg cac atc tcg gag aac tcc ttt ggg ccg tct ggg ggc 3931 Gly Thr Leu Arg His Ile Ser Glu Asn Ser Phe Gly Pro Ser Gly Gly 1225 1230 1235 ctg cgg gaa gga agc ctg agt tct caa gat tcc agg act gag agt gcc 3979 Leu Arg Glu Gly Ser Leu Ser Ser Gln Asp Ser Arg Thr Glu Ser Ala 1240 1245 1250 agc ttg tct caa agc cag gtc aat ggt ttc ttt gcc agc cat tta ggt 4027 Ser Leu Ser Gln Ser Gln Val Asn Gly Phe Phe Ala Ser His Leu Gly 1255 1260 1265 1270 gac caa acc tgg cag gaa tca cag cat ggc agc cct tcc cca tct gta 4075 Asp Gln Thr Trp Gln Glu Ser Gln His Gly Ser Pro Ser Pro Ser Val 1275 1280 1285 ata tcc aaa gcc acc gag aaa gag act ttc act gat agt aac caa agc 4123 Ile Ser Lys Ala Thr Glu Lys Glu Thr Phe Thr Asp Ser Asn Gln Ser 1290 1295 1300 aaa act aaa aag cca ggc att tct gat gta act gat tac tca gac cgt 4171 Lys Thr Lys Lys Pro Gly Ile Ser Asp Val Thr Asp Tyr Ser Asp Arg 1305 1310 1315 gga gat tca gac atg gat gaa gcc act tac tcc agc agt cag gat cat 4219 Gly Asp Ser Asp Met Asp Glu Ala Thr Tyr Ser Ser Ser Gln Asp His 1320 1325 1330 caa aca cca aaa cag gaa tct tcc tct tca gtg aat aca tcc aac aag 4267 Gln Thr Pro Lys Gln Glu Ser Ser Ser Ser Val Asn Thr Ser Asn Lys 1335 1340 1345 1350 atg aat ttt aaa act ttt tct tca tca cct cct aag cct gga gat atc 4315 Met Asn Phe Lys Thr Phe Ser Ser Ser Pro Pro Lys Pro Gly Asp Ile 1355 1360 1365 ttt gag gtt gaa ctg gct aaa aat gat aac agc ttg ggg ata agt gtc 4363 Phe Glu Val Glu Leu Ala Lys Asn Asp Asn Ser Leu Gly Ile Ser Val 1370 1375 1380 acg gta ctg ttt gac aag gga ggt gtg aat acg agt gtc aga cat ggt 4411 Thr Val Leu Phe Asp Lys Gly Gly Val Asn Thr Ser Val Arg His Gly 1385 1390 1395 ggc att tat gtg aaa gct gtt att ccc cag gga gca gca gag tct gat 4459 Gly Ile Tyr Val Lys Ala Val Ile Pro Gln Gly Ala Ala Glu Ser Asp 1400 1405 1410 ggt aga att cac aaa ggt gat cgc gtc cta gct gtc aat gga gtt agt 4507 Gly Arg Ile His Lys Gly Asp Arg Val Leu Ala Val Asn Gly Val Ser 1415 1420 1425 1430 cta gaa gga gcc acc cat aag caa gct gtg gaa aca ctg aga aat aca 4555 Leu Glu Gly Ala Thr His Lys Gln Ala Val Glu Thr Leu Arg Asn Thr 1435 1440 1445 gga cag gtg gtt cat ctg tta tta gaa aag gga caa tct cca aca tct 4603 Gly Gln Val Val His Leu Leu Leu Glu Lys Gly Gln Ser Pro Thr Ser 1450 1455 1460 aaa gaa cat gtc ccg gta acc cca cag tgt acc ctt tca gat cag aat 4651 Lys Glu His Val Pro Val Thr Pro Gln Cys Thr Leu Ser Asp Gln Asn 1465 1470 1475 gcc caa ggt caa ggc cca gaa aaa gtg aag aaa aca act cag gtc aaa 4699 Ala Gln Gly Gln Gly Pro Glu Lys Val Lys Lys Thr Thr Gln Val Lys 1480 1485 1490 gac tac agc ttt gtc act gaa gaa aat aca ttt gag gta aaa tta ttt 4747 Asp Tyr Ser Phe Val Thr Glu Glu Asn Thr Phe Glu Val Lys Leu Phe 1495 1500 1505 1510 aaa aat agc tca ggt cta gga ttc agt ttt tct cga gaa gat aat ctt 4795 Lys Asn Ser Ser Gly Leu Gly Phe Ser Phe Ser Arg Glu Asp Asn Leu 1515 1520 1525 ata ccg gag caa att aat gcc agc ata gta agg gtt aaa aag ctc ttt 4843 Ile Pro Glu Gln Ile Asn Ala Ser Ile Val Arg Val Lys Lys Leu Phe 1530 1535 1540 cct gga cag cca gca gca gaa agt gga aaa att gat gta gga gat gtt 4891 Pro Gly Gln Pro Ala Ala Glu Ser Gly Lys Ile Asp Val Gly Asp Val 1545 1550 1555 atc ttg aaa gtg aat gga gcc tct ttg aaa gga cta tct cag cag gaa 4939 Ile Leu Lys Val Asn Gly Ala Ser Leu Lys Gly Leu Ser Gln Gln Glu 1560 1565 1570 gtc ata tct gct ctc agg gga act gct cca gaa gta ttc ttg ctt ctc 4987 Val Ile Ser Ala Leu Arg Gly Thr Ala Pro Glu Val Phe Leu Leu Leu 1575 1580 1585 1590 tgc aga cct cca cct ggt gtg cta ccg gaa att gat act gcg ctt ttg 5035 Cys Arg Pro Pro Pro Gly Val Leu Pro Glu Ile Asp Thr Ala Leu Leu 1595 1600 1605 acc cca ctt cag tct cca gca caa gta ctt cca aac agc agt aaa gac 5083 Thr Pro Leu Gln Ser Pro Ala Gln Val Leu Pro Asn Ser Ser Lys Asp 1610 1615 1620 tct tct cag cca tca tgt gtg gag caa agc acc agc tca gat gaa aat 5131 Ser Ser Gln Pro Ser Cys Val Glu Gln Ser Thr Ser Ser Asp Glu Asn 1625 1630 1635 gaa atg tca gac aaa agc aaa aaa cag tgc aag tcc cca tcc aga aga 5179 Glu Met Ser Asp Lys Ser Lys Lys Gln Cys Lys Ser Pro Ser Arg Arg 1640 1645 1650 gac agt tac agt gac agc agt ggg agt gga gaa gat gac tta gtg aca 5227 Asp Ser Tyr Ser Asp Ser Ser Gly Ser Gly Glu Asp Asp Leu Val Thr 1655 1660 1665 1670 gct cca gca aac ata tca aat tcg acc tgg agt tca gct ttg cat cag 5275 Ala Pro Ala Asn Ile Ser Asn Ser Thr Trp Ser Ser Ala Leu His Gln 1675 1680 1685 act cta agc aac atg gta tca cag gca cag agt cat cat gaa gca ccc 5323 Thr Leu Ser Asn Met Val Ser Gln Ala Gln Ser His His Glu Ala Pro 1690 1695 1700 aag agt caa gaa gat acc att tgt acc atg ttt tac tat cct cag aaa 5371 Lys Ser Gln Glu Asp Thr Ile Cys Thr Met Phe Tyr Tyr Pro Gln Lys 1705 1710 1715 att ccc aat aaa cca gag ttt gag gac agt aat cct tcc cct cta cca 5419 Ile Pro Asn Lys Pro Glu Phe Glu Asp Ser Asn Pro Ser Pro Leu Pro 1720 1725 1730 ccg gat atg gct cct ggg cag agt tat caa ccc caa tca gaa tct gct 5467 Pro Asp Met Ala Pro Gly Gln Ser Tyr Gln Pro Gln Ser Glu Ser Ala 1735 1740 1745 1750 tcc tct agt tcg atg gat aag tat cat ata cat cac att tct gaa cca 5515 Ser Ser Ser Ser Met Asp Lys Tyr His Ile His His Ile Ser Glu Pro 1755 1760 1765 act aga caa gaa aac tgg aca cct ttg aaa aat gac ttg gaa aat cac 5563 Thr Arg Gln Glu Asn Trp Thr Pro Leu Lys Asn Asp Leu Glu Asn His 1770 1775 1780 ctt gaa gac ttt gaa ctg gaa gta gaa ctc ctc att acc cta att aaa 5611 Leu Glu Asp Phe Glu Leu Glu Val Glu Leu Leu Ile Thr Leu Ile Lys 1785 1790 1795 tca gaa aaa gga agc ctg ggt ttt aca gta acc aaa ggc aat cag aga 5659 Ser Glu Lys Gly Ser Leu Gly Phe Thr Val Thr Lys Gly Asn Gln Arg 1800 1805 1810 att ggt tgt tat gtt cat gat gtc ata cag gat cca gcc aaa agt gat 5707 Ile Gly Cys Tyr Val His Asp Val Ile Gln Asp Pro Ala Lys Ser Asp 1815 1820 1825 1830 gga agg cta aaa cct ggg gac cgg ctc ata aag gtt aat gat aca gat 5755 Gly Arg Leu Lys Pro Gly Asp Arg Leu Ile Lys Val Asn Asp Thr Asp 1835 1840 1845 gtt act aat atg act cat aca gat gca gtt aat ctg ctc cgg gct gca 5803 Val Thr Asn Met Thr His Thr Asp Ala Val Asn Leu Leu Arg Ala Ala 1850 1855 1860 tcc aaa aca gtc aga tta gtt att gga cga gtt cta gaa tta ccc aga 5851 Ser Lys Thr Val Arg Leu Val Ile Gly Arg Val Leu Glu Leu Pro Arg 1865 1870 1875 ata cca atg ttg cct cat ttg cta ccg gac ata aca cta acg tgc aac 5899 Ile Pro Met Leu Pro His Leu Leu Pro Asp Ile Thr Leu Thr Cys Asn 1880 1885 1890 aaa gag gag ttg ggt ttt tcc tta tgt gga ggt cat gac agc ctt tat 5947 Lys Glu Glu Leu Gly Phe Ser Leu Cys Gly Gly His Asp Ser Leu Tyr 1895 1900 1905 1910 caa gtg gta tat att agt gat att aat cca agg tcc gtc gca gcc att 5995 Gln Val Val Tyr Ile Ser Asp Ile Asn Pro Arg Ser Val Ala Ala Ile 1915 1920 1925 gag ggt aat ctc cag cta tta gat gtc atc cat tat gtg aac gga gtc 6043 Glu Gly Asn Leu Gln Leu Leu Asp Val Ile His Tyr Val Asn Gly Val 1930 1935 1940 agc aca caa gga atg acc ttg gag gaa gtt aac aga gca tta gac atg 6091 Ser Thr Gln Gly Met Thr Leu Glu Glu Val Asn Arg Ala Leu Asp Met 1945 1950 1955 tca ctt cct tca ttg gta ttg aaa gca aca aga aat gat ctt cca gtg 6139 Ser Leu Pro Ser Leu Val Leu Lys Ala Thr Arg Asn Asp Leu Pro Val 1960 1965 1970 gtc ccc agc tca aag agg tct gct gtt tca gct cca aag tca acc aaa 6187 Val Pro Ser Ser Lys Arg Ser Ala Val Ser Ala Pro Lys Ser Thr Lys 1975 1980 1985 1990 ggc aat ggt tcc tac agt gtg ggg tct tgc agc cag cct gcc ctc act 6235 Gly Asn Gly Ser Tyr Ser Val Gly Ser Cys Ser Gln Pro Ala Leu Thr 1995 2000 2005 cct aat gat tca ttc tcc acg gtt gct ggg gaa gaa ata aat gaa ata 6283 Pro Asn Asp Ser Phe Ser Thr Val Ala Gly Glu Glu Ile Asn Glu Ile 2010 2015 2020 tcg tac ccc aaa gga aaa tgt tct act tat cag ata aag gga tca cca 6331 Ser Tyr Pro Lys Gly Lys Cys Ser Thr Tyr Gln Ile Lys Gly Ser Pro 2025 2030 2035 aac ttg act ctg ccc aaa gaa tct tat ata caa gaa gat gac att tat 6379 Asn Leu Thr Leu Pro Lys Glu Ser Tyr Ile Gln Glu Asp Asp Ile Tyr 2040 2045 2050 gat gat tcc caa gaa gct gaa gtt atc cag tct ctg ctg gat gtt gtg 6427 Asp Asp Ser Gln Glu Ala Glu Val Ile Gln Ser Leu Leu Asp Val Val 2055 2060 2065 2070 gat gag gaa gcc cag aat ctt tta aac gaa aat aat gca gca gga tac 6475 Asp Glu Glu Ala Gln Asn Leu Leu Asn Glu Asn Asn Ala Ala Gly Tyr 2075 2080 2085 tcc tgt ggt cca ggt aca tta aag atg aat ggg aag tta tca gaa gag 6523 Ser Cys Gly Pro Gly Thr Leu Lys Met Asn Gly Lys Leu Ser Glu Glu 2090 2095 2100 aga aca gaa gat aca gac tgc gat ggt tca cct tta cct gag tat ttt 6571 Arg Thr Glu Asp Thr Asp Cys Asp Gly Ser Pro Leu Pro Glu Tyr Phe 2105 2110 2115 act gag gcc acc aaa atg aat ggc tgt gaa gaa tat tgt gaa gaa aaa 6619 Thr Glu Ala Thr Lys Met Asn Gly Cys Glu Glu Tyr Cys Glu Glu Lys 2120 2125 2130 gta aaa agt gaa agc tta att cag aag cca caa gaa aag aag act gat 6667 Val Lys Ser Glu Ser Leu Ile Gln Lys Pro Gln Glu Lys Lys Thr Asp 2135 2140 2145 2150 gat gat gaa ata aca tgg gga aat gat gag ttg cca ata gag aga aca 6715 Asp Asp Glu Ile Thr Trp Gly Asn Asp Glu Leu Pro Ile Glu Arg Thr 2155 2160 2165 aac cat gaa gat tct gat aaa gat cat tcc ttt ctg aca aac gat gag 6763 Asn His Glu Asp Ser Asp Lys Asp His Ser Phe Leu Thr Asn Asp Glu 2170 2175 2180 ctc gct gta ctc cct gtc gtc aaa gtg ctt ccc tct ggt aaa tac acg 6811 Leu Ala Val Leu Pro Val Val Lys Val Leu Pro Ser Gly Lys Tyr Thr 2185 2190 2195 ggt gcc aac tta aaa tca gtc att cga gtc ctg cgg ggt ttg cta gat 6859 Gly Ala Asn Leu Lys Ser Val Ile Arg Val Leu Arg Gly Leu Leu Asp 2200 2205 2210 caa gga att cct tct aag gag ctg gag aat ctt caa gaa tta aaa cct 6907 Gln Gly Ile Pro Ser Lys Glu Leu Glu Asn Leu Gln Glu Leu Lys Pro 2215 2220 2225 2230 ttg gat cag tgt cta att ggg caa act aag gaa aac aga agg aag aac 6955 Leu Asp Gln Cys Leu Ile Gly Gln Thr Lys Glu Asn Arg Arg Lys Asn 2235 2240 2245 aga tat aaa aat ata ctt ccc tat gat gct aca aga gtg cct ctt gga 7003 Arg Tyr Lys Asn Ile Leu Pro Tyr Asp Ala Thr Arg Val Pro Leu Gly 2250 2255 2260 gat gaa ggt ggc tat atc aat gcc agc ttc att aag ata cca gtt ggg 7051 Asp Glu Gly Gly Tyr Ile Asn Ala Ser Phe Ile Lys Ile Pro Val Gly 2265 2270 2275 aaa gaa gag ttc gtt tac att gcc tgc caa gga cca ctg cct aca act 7099 Lys Glu Glu Phe Val Tyr Ile Ala Cys Gln Gly Pro Leu Pro Thr Thr 2280 2285 2290 gtt gga gac ttc tgg cag atg att tgg gag caa aaa tcc aca gtg ata 7147 Val Gly Asp Phe Trp Gln Met Ile Trp Glu Gln Lys Ser Thr Val Ile 2295 2300 2305 2310 gcc atg atg act caa gaa gta gaa gga gaa aaa atc aaa tgc cag cgc 7195 Ala Met Met Thr Gln Glu Val Glu Gly Glu Lys Ile Lys Cys Gln Arg 2315 2320 2325 tat tgg ccc aac atc cta ggc aaa aca aca atg gtc agc aac aga ctt 7243 Tyr Trp Pro Asn Ile Leu Gly Lys Thr Thr Met Val Ser Asn Arg Leu 2330 2335 2340 cga ctg gct ctt gtg aga atg cag cag ctg aag ggc ttt gtg gtg agg 7291 Arg Leu Ala Leu Val Arg Met Gln Gln Leu Lys Gly Phe Val Val Arg 2345 2350 2355 gca atg acc ctt gaa gat att cag acc aga gag gtg cgc cat att tct 7339 Ala Met Thr Leu Glu Asp Ile Gln Thr Arg Glu Val Arg His Ile Ser 2360 2365 2370 cat ctg aat ttc act gcc tgg cca gac cat gat aca cct tct caa cca 7387 His Leu Asn Phe Thr Ala Trp Pro Asp His Asp Thr Pro Ser Gln Pro 2375 2380 2385 2390 gat gat ctg ctt act ttt atc tcc tac atg aga cac atc cac aga tca 7435 Asp Asp Leu Leu Thr Phe Ile Ser Tyr Met Arg His Ile His Arg Ser 2395 2400 2405 ggc cca atc att acg cac tgc agt gct ggc att gga cgt tca ggg acc 7483 Gly Pro Ile Ile Thr His Cys Ser Ala Gly Ile Gly Arg Ser Gly Thr 2410 2415 2420 ctg att tgc ata gat gtg gtt ctg gga tta atc agt cag gat ctt gat 7531 Leu Ile Cys Ile Asp Val Val Leu Gly Leu Ile Ser Gln Asp Leu Asp 2425 2430 2435 ttt gac atc tct gat ttg gtg cgc tgc atg aga cta caa aga cac gga 7579 Phe Asp Ile Ser Asp Leu Val Arg Cys Met Arg Leu Gln Arg His Gly 2440 2445 2450 atg gtt cag aca gag gat caa tat att ttc tgc tat caa gtc atc ctt 7627 Met Val Gln Thr Glu Asp Gln Tyr Ile Phe Cys Tyr Gln Val Ile Leu 2455 2460 2465 2470 tat gtc ctg aca cgt ctt caa gca gaa gaa gag caa aaa cag cag cct 7675 Tyr Val Leu Thr Arg Leu Gln Ala Glu Glu Glu Gln Lys Gln Gln Pro 2475 2480 2485 cag ctt ctg aag tga catgaaaaga gcctctggat gcatttccat ttctctcctt 7730 Gln Leu Leu Lys 2490 aacctccagc agactcctgc tctctatcca aaataagatc acagagcagc aagttcatac 7790 aacatgcatg ttctcctcta tcttagaggg gtattcttct tgaaaataaa aaatattgaa 7850 atgctgtatt tttacagcta ctttaaccta tgataattat ttacaaaatt ttaacactaa 7910 ccaaacaatg cagatcttag ggatgattaa aggcagcatt tgatgatagc agacattgtt 7970 acaaggacat ggtgagtcta tttttaatgc accaatcttg tttatagcaa aaatgttttc 8030 caatatttta ataaagtagt tattttatag gggatacttg aaaccagtat ttaagcttta 8090 aatgacagta atattggcat agaaaaaagt agcaaatgtt tactgtatca atttctaatg 8150 tttactatat agaatttcct gtaatatatt tatatacttt ttcatgaaaa tggagttatc 8210 agttatctgt ttgttactgc atcatctgtt tgtaatcatt atctcacttt gtaaataaaa 8270 acacacctta aaacatg 8287 <210> SEQ ID NO 13 <220> FEATURE: <400> SEQUENCE: 13 000 <210> SEQ ID NO 14 <220> FEATURE: <400> SEQUENCE: 14 000 <210> SEQ ID NO 15 <220> FEATURE: <400> SEQUENCE: 15 000 <210> SEQ ID NO 16 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 16 catggaaagc gaaggaccaa 20 <210> SEQ ID NO 17 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 17 atctagcaaa ccccgcagga 20 <210> SEQ ID NO 18 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 18 ccgtggagaa tgaatcatta 20 <210> SEQ ID NO 19 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 19 ggtggctgac tccctccaga 20 <210> SEQ ID NO 20 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 20 cattttcatg aaaaagtata 20 <210> SEQ ID NO 21 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 21 ttcaggttca ctaaggtgat 20 <210> SEQ ID NO 22 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 22 agcagagact ggataacttc 20 <210> SEQ ID NO 23 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 23 agtctcatca tcacagtgca 20 <210> SEQ ID NO 24 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 24 agcttgctta tgggtggctc 20 <210> SEQ ID NO 25 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 25 attctgggta attctagaac 20 <210> SEQ ID NO 26 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 26 ctaatctgac tgttttggat 20 <210> SEQ ID NO 27 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 27 gatttcccag aaccagtttt 20 <210> SEQ ID NO 28 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 28 aggaaagagc tttttaaccc 20 <210> SEQ ID NO 29 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 29 gcatgtagga agatttcttc 20 <210> SEQ ID NO 30 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 30 tattttggat agagagcagg 20 <210> SEQ ID NO 31 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 31 tcaagcatcc atccaagtca 20 <210> SEQ ID NO 32 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 32 agcaaatgag gcaacattgg 20 <210> SEQ ID NO 33 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 33 cagtgaatgc tcgaagatcc 20 <210> SEQ ID NO 34 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 34 ttttaagttg gcacccgtgt 20 <210> SEQ ID NO 35 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 35 aagggtgttt catattgtct 20 <210> SEQ ID NO 36 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 36 ccagtggtga tccttggaag 20 <210> SEQ ID NO 37 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 37 agatgaacca cctgtcctgt 20 <210> SEQ ID NO 38 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 38 gtttgttgag ggtgctgctg 20 <210> SEQ ID NO 39 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 39 tcttgccgtt ttagcatgat 20 <210> SEQ ID NO 40 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 40 gctgagatag tcctttcaaa 20 <210> SEQ ID NO 41 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 41 cggtccccag gttttagcct 20 <210> SEQ ID NO 42 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 42 acctctctgg tctgaatatc 20 <210> SEQ ID NO 43 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 43 agccatgttt tattccatct 20 <210> SEQ ID NO 44 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 44 ctgataactt cccattcatc 20 <210> SEQ ID NO 45 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 45 ctaagataga ggagaacatg 20 <210> SEQ ID NO 46 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 46 ctcatgcagc gcaccaaatc 20 <210> SEQ ID NO 47 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 47 tttctgagga tagtaaaaca 20 <210> SEQ ID NO 48 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 48 atggactttc actggaggta 20 <210> SEQ ID NO 49 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 49 gagaataaat gtggatcttt 20 <210> SEQ ID NO 50 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 50 caaccgtgga gaatgaatca 20 <210> SEQ ID NO 51 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 51 caaggacacc tttagaacag 20 <210> SEQ ID NO 52 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 52 agaaatccca tagatttact 20 <210> SEQ ID NO 53 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 53 gacacgtgca tattaccggc 20 <210> SEQ ID NO 54 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 54 tatttcttcc tcctgaagtg 20 <210> SEQ ID NO 55 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 55 ggtgggcaat tctcgagtgt 20 <210> SEQ ID NO 56 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 56 gccatgtttt attccatctg 20 <210> SEQ ID NO 57 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 57 gataacaagt gtcacatctt 20 <210> SEQ ID NO 58 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 58 ctctcagtcc tggaatcttg 20 <210> SEQ ID NO 59 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 59 agtaagtggc ttcatccatg 20 <210> SEQ ID NO 60 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 60 ttggtgtttg atgatcctga 20 <210> SEQ ID NO 61 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 61 taaaattcat cttgttggat 20 <210> SEQ ID NO 62 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 62 tgaggatagt aaaacatggt 20 <210> SEQ ID NO 63 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 63 agcagattaa ctgcatctgt 20 <210> SEQ ID NO 64 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 64 caataccaat gaaggaagtg 20 <210> SEQ ID NO 65 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 65 aagattctcc agctccttag 20 <210> SEQ ID NO 66 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 66 gtaaacgaac tcttctttcc 20 <210> SEQ ID NO 67 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 67 ttggcaggca atgtaaacga 20 <210> SEQ ID NO 68 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 68 ttttcatgtc acttcagaag 20 <210> SEQ ID NO 69 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 69 gatctttatt ttggatagag 20 <210> SEQ ID NO 70 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 70 ctactttatt aaaatattgg 20 <210> SEQ ID NO 71 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 71 ctgtcattta aagcttaaat 20 <210> SEQ ID NO 72 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 72 caaacagatg atgcagtaac 20 <210> SEQ ID NO 73 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 73 gtttttattt acaaagtgag 20 <210> SEQ ID NO 74 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 74 gtcacttcta aaacacattc 20 <210> SEQ ID NO 75 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 75 tattacttac aagaatagac 20 <210> SEQ ID NO 76 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 76 ggatgcttac ctttaaaaat 20 <210> SEQ ID NO 77 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 77 ttgtaaaact ctctcactga 20 <210> SEQ ID NO 78 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 78 gtagaaggca ctaaaagtca 20 <210> SEQ ID NO 79 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 79 aagatcattt ctgtgttgta 20 <210> SEQ ID NO 80 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 80 caagctgcag tgtcacaggt 20 <210> SEQ ID NO 81 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 81 ccattattat tgtgtaggag 20 <210> SEQ ID NO 82 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 82 tccaaatgga agatcagagg 20 <210> SEQ ID NO 83 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 83 aagtggtggc aatttcctaa 20 <210> SEQ ID NO 84 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 84 gagcttcttc ctggaatgat 20 <210> SEQ ID NO 85 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 85 ggcttttgta tgtctagtac 20 <210> SEQ ID NO 86 <220> FEATURE: <400> SEQUENCE: 86 000 <210> SEQ ID NO 87 <220> FEATURE: <400> SEQUENCE: 87 000 <210> SEQ ID NO 88 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 88 ttggtccttc gctttccatg 20 <210> SEQ ID NO 89 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 89 tcctgcgggg tttgctagat 20 <210> SEQ ID NO 90 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 90 taatgattca ttctccacgg 20 <210> SEQ ID NO 91 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 91 tctggaggga gtcagccacc 20 <210> SEQ ID NO 92 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 92 tgcactgtga tgatgagact 20 <210> SEQ ID NO 93 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 93 gagccaccca taagcaagct 20 <210> SEQ ID NO 94 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 94 gttctagaat tacccagaat 20 <210> SEQ ID NO 95 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 95 atccaaaaca gtcagattag 20 <210> SEQ ID NO 96 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 96 aaaactggtt ctgggaaatc 20 <210> SEQ ID NO 97 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 97 gaagaaatct tcctacatgc 20 <210> SEQ ID NO 98 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 98 cctgctctct atccaaaata 20 <210> SEQ ID NO 99 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 99 tgacttggat ggatgcttga 20 <210> SEQ ID NO 100 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 100 ccaatgttgc ctcatttgct 20 <210> SEQ ID NO 101 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 101 ggatcttcga gcattcactg 20 <210> SEQ ID NO 102 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 102 acacgggtgc caacttaaaa 20 <210> SEQ ID NO 103 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 103 agacaatatg aaacaccctt 20 <210> SEQ ID NO 104 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 104 cttccaagga tcaccactgg 20 <210> SEQ ID NO 105 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 105 acaggacagg tggttcatct 20 <210> SEQ ID NO 106 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 106 cagcagcacc ctcaacaaac 20 <210> SEQ ID NO 107 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 107 atcatgctaa aacggcaaga 20 <210> SEQ ID NO 108 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 108 tttgaaagga ctatctcagc 20 <210> SEQ ID NO 109 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 109 aggctaaaac ctggggaccg 20 <210> SEQ ID NO 110 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 110 gatattcaga ccagagaggt 20 <210> SEQ ID NO 111 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 111 agatggaata aaacatggct 20 <210> SEQ ID NO 112 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 112 gatgaatggg aagttatcag 20 <210> SEQ ID NO 113 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 113 tgttttacta tcctcagaaa 20 <210> SEQ ID NO 114 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 114 tacctccagt gaaagtccat 20 <210> SEQ ID NO 115 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 115 aaagatccac atttattctc 20 <210> SEQ ID NO 116 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 116 tgattcattc tccacggttg 20 <210> SEQ ID NO 117 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 117 ctgttctaaa ggtgtccttg 20 <210> SEQ ID NO 118 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 118 agtaaatcta tgggatttct 20 <210> SEQ ID NO 119 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 119 gccggtaata tgcacgtgtc 20 <210> SEQ ID NO 120 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 120 acactcgaga attgcccacc 20 <210> SEQ ID NO 121 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 121 cagatggaat aaaacatggc 20 <210> SEQ ID NO 122 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 122 aagatgtgac acttgttatc 20 <210> SEQ ID NO 123 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 123 caagattcca ggactgagag 20 <210> SEQ ID NO 124 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 124 catggatgaa gccacttact 20 <210> SEQ ID NO 125 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 125 tcaggatcat caaacaccaa 20 <210> SEQ ID NO 126 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 126 accatgtttt actatcctca 20 <210> SEQ ID NO 127 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 127 acagatgcag ttaatctgct 20 <210> SEQ ID NO 128 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 128 cacttccttc attggtattg 20 <210> SEQ ID NO 129 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 129 ctaaggagct ggagaatctt 20 <210> SEQ ID NO 130 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 130 ggaaagaaga gttcgtttac 20 <210> SEQ ID NO 131 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 131 tcgtttacat tgcctgccaa 20 <210> SEQ ID NO 132 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 132 cttctgaagt gacatgaaaa 20 <210> SEQ ID NO 133 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 133 ctctatccaa aataaagatc 20 <210> SEQ ID NO 134 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 134 atttaagctt taaatgacag 20 <210> SEQ ID NO 135 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 135 ctcactttgt aaataaaaac 20 <210> SEQ ID NO 136 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 136 acctgtgaca ctgcagcttg 20 <210> SEQ ID NO 137 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 137 ttaggaaatt gccaccactt 20 <210> SEQ ID NO 138 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 138 atcattccag gaagaagctc 20 <210> SEQ ID NO 139 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 139 gtactagaca tacaaaagcc 20 

What is claimed is:
 1. A compound 8 to 80 nucleobases in length targeted to a nucleic acid molecule encoding PTPN13, wherein said compound specifically hybridizes with said nucleic acid molecule encoding PTPN13 (SEQ ID NO: 4) and inhibits the expression of PTPN13.
 2. The compound of claim 1 comprising 12 to 50 nucleobases in length.
 3. The compound of claim 2 comprising 15 to 30 nucleobases in length.
 4. The compound of claim 1 comprising an oligonucleotide.
 5. The compound of claim 4 comprising an antisense oligonucleotide.
 6. The compound of claim 4 comprising a DNA oligonucleotide.
 7. The compound of claim 4 comprising an RNA oligonucleotide.
 8. The compound of claim 4 comprising a chimeric oligonucleotide.
 9. The compound of claim 4 wherein at least a portion of said compound hybridizes with RNA to form an oligonucleotide-RNA duplex.
 10. The compound of claim 1 having at least 70% complementarity with a nucleic acid molecule encoding PTPN13 (SEQ ID NO: 4) said compound specifically hybridizing to and inhibiting the expression of PTPN13.
 11. The compound of claim 1 having at least 80% complementarity with a nucleic acid molecule encoding PTPN13 (SEQ ID NO: 4) said compound specifically hybridizing to and inhibiting the expression of PTPN13.
 12. The compound of claim 1 having at least 90% complementarity with a nucleic acid molecule encoding PTPN13 (SEQ ID NO: 4) said compound specifically hybridizing to and inhibiting the expression of PTPN13.
 13. The compound of claim 1 having at least 95% complementarity with a nucleic acid molecule encoding PTPN13 (SEQ ID NO: 4) said compound specifically hybridizing to and inhibiting the expression of PTPN13.
 14. The compound of claim 1 having at least one modified internucleoside linkage, sugar moiety, or nucleobase.
 15. The compound of claim 1 having at least one 2′-O-methoxyethyl sugar moiety.
 16. The compound of claim 1 having at least one phosphorothioate internucleoside linkage.
 17. The compound of claim 1 having at least one 5-methylcytosine.
 18. A method of inhibiting the expression of PTPN13 in cells or tissues comprising contacting said cells or tissues with the compound of claim 1 so that expression of PTPN13 is inhibited.
 19. A method of screening for a modulator of PTPN13, the method comprising the steps of: a. contacting a preferred target segment of a nucleic acid molecule encoding PTPN13 with one or more candidate modulators of PTPN13, and b. identifying one or more modulators of PTPN13 expression which modulate the expression of PTPN13.
 20. The method of claim 19 wherein the modulator of PTPN13 expression comprises an oligonucleotide, an antisense oligonucleotide, a DNA oligonucleotide, an RNA oligonucleotide, an RNA oligonucleotide having at least a portion of said RNA oligonucleotide capable of hybridizing with RNA to form an oligonucleotide-RNA duplex, or a chimeric oligonucleotide.
 21. A diagnostic method for identifying a disease state comprising identifying the presence of PTPN13 in a sample using at least one of the primers comprising SEQ ID NOs: 5 or 6, or the probe comprising SEQ ID NO:
 7. 22. A kit or assay device comprising the compound of claim
 1. 23. A method of treating an animal having a disease or condition associated with PTPN13 comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of claim 1 so that expression of PTPN13 is inhibited.
 24. The method of claim 23 wherein the disease or condition is a hyperproliferative disorder. 